Multiple-symptom medical treatment with roving-based neurostimulation

ABSTRACT

Stimulation treatments for various medical disorders comprise serially varying the stimulation parameters, especially in order to treat multiple symptoms of a disorder. Roving of parameter values can be done in relation to the proportional incidence of the symptoms. Varying the parameters can occur according to algorithms designed in relation to endogenous rhythms of a patient. Especially when using low-frequency stimulation signals the parameter values can be set in order to match or avoid these internal activity patterns and rhythms. These treatment strategies thereby improve the therapeutic efficacy of stimulation or and decrease risk of interference with normal brain, sensory, motor, and cognitive processes. Novel methods are described for choosing, creating and subsequently stimulating with partial signals having unique temporal and spectral profiles which summate to produce desired vector fields, and which may be roved to produce roving vector fields. Stimulation can occur using different devices such as implantable devices or transcranial magnetic stimulators.

This application is a continuation-in-part of application Ser. No.11/307,050 filed Jan. 20, 2006, said application claiming priority ofU.S. Provisional Applications No., 60/594,321 filed on Mar. 29, 2005 and60/596,693 filed on Oct. 13, 2005, all entitled“Systems and Methods forTissue Stimulation in Medical Treatment”, said application also claimingbenefit of 60/593,521 filed Jan. 21, 2005, entitled“Systems and methodsfor treatment of epilepsy and other neurological and psychiatricdisorders”, and this application also claims priority of U.S.Provisional Application No. 60/766,499 filed Jan. 23, 2006 andincorporates all of these applications herein in their entirety.

The invention is generally directed to treatment systems and methodsused to guide stimulation treatments and includes providing, in bothresponsive and non-responsive manners, roving stimulation signals usedby implanted or external stimulation devices such as magneticstimulators. The stimulators can induce electrical fields, gradients,and currents in the brain or body of a patient, and can be used in thetreatment of medical disorders such as neurological, movement, andpsychiatric disorders, or other disorders of the brain or body, and isparticularly relevant to reducing the incidence of epileptic seizures.

BACKGROUND

The measurement and modulation of brain electrical activity have beeninvestigated for close to a century. In general the lower-frequencyendogenous potentials (e.g., 1-10 Hz) have been linked to inhibition andsuppression, and are more prevalent during diminished arousal levels andsleep, while a shift to higher frequency activity, such as beta (e.g.,12-30 Hz) and gamma (e.g. 30-80 Hz) band activity, is associated withincreased arousal and excitation. Neurostimulation which alters theseendogenous frequencies in areas of the brain can be used to modulate therelative arousal level of various brain structures, in the treatment ofdisorders. Different brain disorders can be associated with deviationsin the activity of a particular region of neural tissue compared tothose of healthy brains, and stimulation may attempt to normalize orcompensate for this activity. Neurostimulation may utilize a wide rangeof signals such as pulsatile or sinusoidal waveforms, which can beprovided using low or high repetition/modulation rates. Recently, slowerfrequency neurostimulation has shown promise in the treatment ofdifferent disorders. Although therapy for a disorder may be obtained byneurostimulation, side-effects due to disruption of endogenous activitymay also result. These can include alterations in processes related tolearning, cognition, memory, and attention. Certain side-effects aremore likely with neurostimulation signals which have a primary componentwhich occurs at the same frequencies as endogenous signals, especiallybelow 15 Hz. Adjusting characteristics of the stimulation signal, inrelation to those of endogenous signals, for example, in order to matchor avoid matching certain characteristics of the endogenous signals, maybe increasingly important when providing therapy at these lower rates ofstimulation. Another solution is to rove a parameter of theneurostimulation signals, such as the dominant frequency of pulserepetition rate, to such an extent that a particular type of stimulationdoes not continuously interfere with endogenous potentials. Unlikeconventional neurostimulation protocols which set the stimulationparameters and then provide stimulation in a consistent manner, thecurrent invention describes different methods of roving the stimulationparameters so that the stimulation signals alternate regularly overtime.

Roving of stimulation parameters can be used to address a number of wellknown factors which impede treatment. For example, since mostneurological disorders comprise a cluster of symptoms roving can bedesigned so that the stimulation treatment is provided across time in asequential manner in order to intermittently deter the emergence ofdifferent symptoms. Further, similar symptoms may be related todifferent disorders, and have different underlying biological causes,each of which can be addressed by roving the stimulation parameters tousing parameters which have been empirically shown to decrease thesesymptoms in question. There may be different mechanisms behind differentsymptoms of a disorder which require relatively different treatmentapproaches. The treatment of epilepsy, provides an illustrative example,since therapy has been successfully provided using both slow (e.g. 1 Hz)and fast (e.g. 50 Hz) stimulation rates. Neurostimulation at lower andhigher frequencies may work via several mechanisms such asdepolarization blockade, synaptic inhibition/depression, and modulation,such as entrainment or suppression of endogenous activity and modulationof brain networks. The correct adjustment of neurostimulation parametersfor the treatment of a wide array of disorders may depend upon multiplefactors, and a consideration of the advantages of different stimulationstrategies and signals is important. Strategies which alternate, rovebetween, or synchronously provide two or more stimulation signals mayserve to modulate the brain in different manners and likely offer anumber of advantages over chronic stimulation with a particular signal.

SUMMARY

Illustrative embodiments demonstrate a number of methods which can beused for improving stimulation to treat various disorders. Rovingstrategies are described for decreasing the risk of using ineffectivestimulation parameters, stimulating non-target tissue, development oftolerance to stimulation, and other unwanted side-effects.

Roving methods are described for selecting, and subsequentlyimplementing, useful stimulation parameter values. Selection ofparameter values occur based upon their ability to provide therapeuticbenefit, as may be reflected in good test scores. In one embodiment ofthe method, a treatment parameter value is systematically varied, andsensed data are collected, processed, and scored, in order to determinewhat parameter values most successfully led to desired treatment effects(e.g.,. test scores that met a threshold criteria). These successfulparameters can then be selected (using ranking and/or meta-analysis oftest scores) and relied upon during treatment. In the treatment ofepilepsy, for example, a value of a stimulation parameter, which isassociated with the frequency content of the neurostimulation signal, isroved. This produces signals with spectral energy that varies across aspecified frequency range (e.g., either carrier frequencies ormodulation frequencies are iteratively varied). The sensed data are thenprocessed to determine the stimulation parameter values that led todecreased seizure scores, and the values associated with the lowestscores may then be selected to be used in treatment (e.g. FIG. 12).Treatment programs can alternate between two or more stimulationparameter values to define stimulation signals. Further test scores canbe selected which reflect decreased seizure activity for different typesof seizures. It is a feature of the invention to utilize a treatmentprogram which provides at least two stimulation signals that aredesigned to treat, or designed in relation to the characteristics of,two different symptoms of a disorder. Test scores may also relate todifferent symptoms of other disorders, such as rigidity and tremor as isoften seen in movement disorders.

The invention provides methods and systems for functionally increasingfocal activation. Partial signals are used which summate to createtherapeutic vector signals. The stimulation parameter values fordifferent sets of partial signals can be chosen and testedautomatically, or by a physician or patient. Sets of partial signalswhich provide therapeutic stimulation while not producing, orminimizing, unwanted side-effects can be selected for treatment(“successful parameter values”). The selection of treatment protocolparameters and treatment signals including partial signals, or vectorsignals, can be determined according to methods described herein.Partial stimulation signals of different temporal and frequencycompositions can be selected to increase the transmission of thestimulation signal, to provide excitatory or inhibitory stimulation, andto induce desired temporal patterns of activity within different areasof tissue. Roving of the stimulation parameters of partial signals canbe accomplished so that the characteristics of the vector signals areeither approximately held constant, or are also roved in a fashion thatis either similar or dissimilar to the changes which occur in thepartial signals.

The stimulation methods may occur without relying upon sensed dataobtained from sensors. Alternatively, stimulation parameter values maybe adjusted based upon “sensed activity” which is patient input (e.g.,via an external patient programmer that communicates with an implanteddevice. This input can be obtained using semi-automatic algorithms ormanual methods which are completely under control of the patient.Sensing may occur as therapy progresses or only during assessmentperiods, such as may occur in the presence of a medical practitioner.When the sensed activity concerns neural processes related to cognitivephenomena such as attention and learning (e.g., hippocampal actvity),the stimulation signals which modulate this activity may also produceundesirable side-effects. Interference in endogenous activity may bediminished using roving. For example, the pulse repetition rate of astimulation signal can be intermittently roved between frequencies thatare within and outside of the frequency range that characterizes apatient's theta activity.

While neurostimulation, especially with respect to treatment ofseizures, is emphasized in some of the material here, the treatment ofother disorders of the brain and body are also described and are no lesscentral to many of the advantages of the inventive principles. Thesestimulation techniques can be applied to the brain duringneuromodulation for the treatment of disorders, such as, epilepsy, orcan be used for the treatment of disorders such as cardiac disorderswhich can be treated via central nervous system (CNS) targets or bydirect stimulation of cardiac tissue. The systems and methods of theinvention can also be applied to the vagus and other nerves related tomodulation of the central and peripheral systems (e.g. unilateral orbilateral stimulation of the trigeminal nerves), and can be directedtowards the tissue of the spinal cord. When used with transcranialmagnetic stimulation, stimulation methods can be used to promote andmodulate sedation and anesthesia. Other advantages, novel features, andfurther scope of applicability of the invention will be described in thefollowing illustrations and description.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention and its advantages, thereis provided a detailed description and accompanying drawings ofembodiments which are presently preferred. In illustrations of themethods, when arrows indicate iteration (i.e., a return from later stepsto prior steps), this iteration is understood to be a preferredembodiment, and executing the steps a single time may also be an option.Steps which occur sequentially may also be realized approximatelyconcurrently, or may be repeated several times (e.g., in order toprovide a statistical estimation of a measure by computing the mean)prior to the next step occurring. It is understood that the invention isnot intended to be limited to the precise arrangements, scales, andinstruments shown, wherein:

FIG. 1 shows a schematic illustration of one embodiment of aneurostimulation system which can be used in the current invention;

FIG. 2 a shows a schematic illustration of a system designed to createpartial signals to be used during neurostimulation, which can beimplemented in the stimulation subsystem;

FIG. 2 b shows a schematic representation of a method of using a systemdesigned to create partial signals that are used duringneurostimulation;

FIG. 3A illustrates an embodiment of an implantable stimulation systemincluding a device having 5 electrodes that are implanted in the neuraltissue of a patient;

FIG. 3B illustrates an embodiment of an implantable stimulation systemincluding a device having electrode sets that are implanted for spinalstimulation of a patient;

FIG. 4 a shows examples of partial signals, where signal #1 and signal#2 are partial signals which can be combined to form a vector signalwhich is termed ‘combined signal’, and where the partial signals have asubstantially different frequency content than the combined signal;

FIG. 4 b shows alternative examples of partial signals and vectorsignals;

FIG. 5 a shows a flow diagram of a method designed in accordance with apreferred embodiment of the present invention, wherein two partialsignals are created by adding interference signals to a low frequencybase signal;

FIG. 5 b shows a flow diagram of a method designed in accordance with apreferred embodiment of the present invention, wherein two partialsignals are created by adding interference signals to a high frequencybase signal, and further includes a step of adjusting the signals;

FIG. 6 shows a flow diagram of an alternative method designed inaccordance with a preferred embodiment of the present invention, whereintwo partial signals are created by deconstructing or modifying a basesignal, and wherein these partial signals are re-assigned to differentcontacts at different moments in time;

FIG. 7 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein thestimulation signal is roved across a frequency range, or alternatedbetween at least two frequencies, during the therapy;

FIG. 8 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein senseddata indicate the proportion of time during which 2 or more medicalevents occur, and stimulation occurs based upon this proportion;

FIG. 9 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein thestimulation signal is temporally distributed across a number ofstimulation locations;

FIG. 10 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein thestimulation signal is modified to either positively or negativelyreinforce endogenous rhythms of sensed data, and which may be appliedwith a specified phase or temporal relationship;

FIG. 11 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein thestimulation signal is selected, created, or created from the senseddata, to either positively or negatively reinforce endogenous rhythms,and which may be applied with a specified phase relationship;

FIG. 12 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein thestimulation signal is adjusted, based upon comparing test data topreviously sensed data, to provide improved therapeutic benefit;

FIG. 13 shows a flow diagram of another method designed in accordancewith a preferred embodiment of the present invention, wherein the two ormore parameters of the stimulation are selected or adjusted, based uponevaluation of sensed data, to provide improved therapeutic benefit;

FIG. 14 shows a flow diagram of an alternative method designed inaccordance with a preferred embodiment of the present invention, inwhich rather than relying upon the creation of new stimulation signals,stimulation signals are modified before being applied in order to alterthe stimulation signals at different moments in time;

FIG. 15 shows a device for providing transcranial magnetic stimulationto a patient; and,

DETAILED DESCRIPTION

FIG. 1 is an overall block diagram of the implantable device 10 a usedfor providing treatment-related functions such as stimulation which canoccur independently or in response to sensing and evaluation of data. Inhousing 11 of the device 10 a several subsystems and modules worktogether to provide therapy. ‘Modules’ may be software subroutines andhardware components which are designed to achieve features of theinvention. The device 10 a may be configured simply to providestimulation treatment or may provide for both sensing and stimulation(SEST) operations. The control of sensing, evaluation, and stimulationis accomplished by the control subsystem 12, which operates according tothe treatment program 300. The control subsystem 12 communicates withand controls the sensing 16 and stimulation 14 subsystems so that theseperform SEST operations.

The control subsystem 12 implements the treatment program 300 whichincludes the subroutines, algorithms, protocols and protocol parametervalues needed to accomplish calibration and operation of the system 10 ain the provision of treatment. The treatment program 300 can selectvarious treatment protocols including the sensing, evaluation andstimulation protocols, and the respective parameter values, which areused by those subsystems. The control subsystem 12 is functionallyconnected, either directly or indirectly, to all the other subsystemsand components within the device 10 a, for achieving control andcommunication operations inherent in providing therapy. The treatmentprogram 300 allows the control subsystem 12 to control and coordinateall functions carried out by various subsystems of the system 10 a, 500.

At various times prior to, during, or after implantation, the treatmentprogram 300 can be programmed to select or adjust treatment protocols inrelation to predetermined times of day and durations (e.g., time sincethe last stimulation protocol was selected). Additionally, the patientmay use a patient programmer 500 to select and adjust the treatmentprogram's protocols 300. The control subsystem 12 can include rovingmodule 300 which contains algorithms and parameters for implementingroving-based treatment, and a roving test module 304, for allowingtesting, evaluation of roving test results, selection of successfulroving parameter values, and storage of information related to rovingtest results. The control subsystem 12 can also contain a partial module42 b that is used in the creation, calibration, testing and adjustmentof partial signals. The partial module 42 b collaborates with partialmodule 42 a of the stimulation subsystem in order to operationallygenerate the partial signals according to methods described herein.

The various treatment protocols and their parameter values are stored inthe memory 20, which is preferably realized as a programmable andquerieable database. The control subsystem 12 can access this memory 20to select information such as“candidate protocol parameter values”,self-norm data values, customizable stimulation routines and protocols,treatment threshold values, and other settings and subroutines which arestored and retrieved during the provision of therapy. The controlsubsystem can also utilize the memory 28 to keep a record of the resultsof evaluation subsystem 18 such as past detected events, features andstatistical measures computed upon these features, self-populationnormative data, and other information related to the evaluation ofsensed signals (e.g., event occurrences, durations, times and counts).The historical record may also contain events marked by the patientusing the external programmer 500 and a record of stimulationtreatments. This historical record can be used to evaluate, and maycause the treatment program 300 to adjust, therapy based upon thisevaluation. For example, if analysis of this“event history” shows arecent increase in event incidence which is above a pre-specified value,or which meets a statistically-based treatment criterion which indicatesa significant increase in events over time has occurred, then a changein stimulation protocol may be implemented according the treatmentprogram. A change in stimulation protocol can include a change in theroving stimulation parameters values, a change the rates of roving,times between roving operations, or may cause a change in thecharacteristics of the partial signals which are used.

The memory subsystem 20 can contain test results from roving tests, testresults relating to the efficacy of combinations of partial signals, aswell as different sets of roving and partial signal parameter values.Data stored in a memory subsystem 20 may be retrieved by the patient'sphysician or by the patient through the communication subsystem 24. Asoftware operating program run by the external patient programmer 500allows the physician to request the sending of historical events anddata including sensed information before, during, and after eachdetected event, as well as specific information relating to thedetection of each event.

The device 10 a may provide therapy using stimulation alone or usingboth stimulation and sensing operations. The sensing subsystem 16 iscapable of being physically and electrically coupled directly to aplurality of sensor probes 34 a, 34 b. In one variation, the sensor 34 acan be an accelerometer which is within the housing 11 and sensor 34 bcan be SEST-conduit which is a multi-stranded electrode lead having aplurality of contacts at its distal ends and is attached at its proximalend to a sensor attachment means in the housing 11.

For most SEST-operations the SEST-signals will be transduced, processed,conditioned, and routed by the SEST-interface 44 a. The SEST-interfaceoperates under control of the sensing and stimulation subsystems toaccomplish therapy operations defined by the treatment program 300. Forexample, the sensing and evaluation subsystems 16, 18 can operate theSEST-interface 44 a in order to evaluate the incoming signals accordingto the parameters of the sensing protocol, and the same is true for thestimulation subsystem 14, with respect to the generation of thestimulation signals. The SEST-signals are guided between the SEST-probes31, 32 and the sensing 16 and stimulation 14 subsystems under control ofthe routing manager 44 b.

The SEST-interface 44 a not only routes incoming signals (from sensors)and outgoing signals (to stimulators) to selected SEST-probes but alsoconditions signals using a signal conditioning (SC) module 310 thatprovides any operations not present in the SEST subsystems 14, 16including but not limited to amplification, for control of, polarity,anode/ cathode/ground/and isolation assignments, current and voltageregulation, analog-to-digital conversion, digital-to-analogtransduction, and charge-balancing functions. Low level multiplexing,port/bus communication, address and control line operations, and routingfunctions are accomplished by the I/O module 312. The SC module 310 cancontain programmable amplifiers, filters, and digital and analog signalprocessing (DSP/ASP) circuitry. Circuitry related to impedance testingand calibration can also be provided to assist in implementing theintended stimulation and calibration routines. The SC module 310contains modules for allowing the stimulation subsystem to createmodulated signals such as amplitude and frequency modulated signals, andto create carrier signals which are stable or which rove over time, andwhich may be bandwidth modulated to adjust the span of their frequencycontent. In general, the SC module 310 provides hardware and relatedoperations that are required for a proper interface with tissue andwhich are not provided by any other subsystem of the device 10 a.

The stimulation subsystem 14 and sensing subsystem 16 are capable ofperforming SEST-operations using a number of different types ofSEST-modules 30 a-e that communicate with SEST-probes 31 a-e that areimplanted in target locations. The SEST-probes 31, 32 are configured foreither sensing or stimulation of tissue, or both. The SEST-interface 44a can communicate with, control, and provide power to SEST-modules 30and SEST-probes 31 and can establish communication with either thesensing 16 or stimulation 14 subsystem. FIG. 1 shows a thermalSEST-module 30 a (e.g., Peltier junction or thermocouple), an opticalSEST-module 30 b, a chemical SEST-module (which may include a reservoirand programmable pump) 30 c, a sonic (including ultrasonic) SEST module30 d, and an electrical/electromagnetic SEST module 30 e. AdditionalSEST modules 30 are also possible (e.g., additional visual, or tactilesignals in order to provide somatosensory stimulation to locations otherthan the brain). The thermal probe 31 a contains a SEST-element whichcan be a thermally conductive surface. The optical probe 31 b contains aSEST-element and may have optical adjustment components such as aprogrammable aperture or biocompatible lens at its distal tip throughwhich light is presented. The optical SEST-module 30 b communication mayinclude power, communication, control, and sensed signals that aresensed by the optical probe 31 b which are relayed to the SEST-interface44 a, and then to subsystems of the device by the routing manager 44 b.The optical SEST-module may also provide a light source to the opticalprobe 31 b. The optical probe 31 b can be a single optical sensor or canbe several sensors. The chemical probe 31 c may be a stimulation conduitwhich is a catheter that may or may not have valve devices foroutputting drugs (used either alone or in conjunction with other typesof stimulation including stimulation which can activate the drug) atspecified stimulation output sites, as well as a chemical sensor. Thesensors 34, SEST-modules 30 and SEST-probes 31, 32 may be located withinthe device 10 a, or may be implanted elsewhere and controlled by thedevice, and may also deliver stimulation therapy themselves

A SEST-probe may also contain processing circuitry for accomplishing thesensing and stimulation and for switching between the sensing andstimulation activities and for transducing the signals. In the varioustypes of sensed data described herein (e.g., electrical impedanceplethysmography, etc.) the data is often measured relatively, such asaccording to baseline measurements, rather than as an absolute value,and can also be adjusted (e.g., calibrated) according to measuredvariance so that the signals are meaningful. When SEST-probes 31 containa plurality of contact elements, the SEST-modules 30 can be programmedso that stimulation is applied according to roving and partial signalmethods. Some probes that may be used by the device have been listed inU.S. Publication No.2005/0277912 to John, which is hereby incorporatedby reference in its entirety.

When used to treat seizures, at least one SEST-probe 31 can be situatedin a brain region, in order to sense activity from an epileptogenicregion, a spike focus, a focal functional deficit, an irritative zone, astructure of the limbic system or the temporal lobe, or any structurewhich is characterized by abnormal electrical or neurochemical activity.Stimulation can occur using a SEST-probe 31 configured to stimulate thebrain, and/or cranial and vagus nerves. When used to treat pain, oneSEST-probe 31 can be in the brain, spine or peripheral nerves, to detectsymptoms related to pain, and the stimulation electrodes can be locatedto stimulate target areas such as the spine. When the disorder is painthe particular symptom types can be related to the type, location, size,quality and duration of pain symptom. Although pain symptoms can includephysiological and biological correlates of pain, the symptoms can bedetected and quantified according to patient input via the patientprogrammer 500. When used to treat tremor or movement disorders, aSEST-probe 31 can be located in a limb manifesting symptoms of thedisorder, proximate to the motor or pre-motor cortex, or in a region ofthe brain having, for example, excessive synchronous activity related tothe frequency of a tremor. When used to promote chemotherapy, a drugSEST-probe 31 c can be in a region near a tumor.

The sensing subsystem 16 senses data according to the parameters of asensing protocol. Sensed data may be comprised of ongoing activity oractivity related to stimulation (e.g., a short post-stimulation blankingperiod may be used to avoid saturation of the amplifier when bothsensing and stimulation occur in the electrical modality). Sensed datamay include, but are not limited to, EEG data, neuronal recordings(e.g., single neuron recordings, nerve potential recordings, local fieldpotential recordings), ultrasound data, oximetry data, optical sensingdata, blood pressure recordings, impedance measurements, measurements oftemperature and acceleration, measurements of emitted or absorbedradiation (e.g., infrared spectroscopy measurements andspectrophotometric measurements), and combinations thereof.

The evaluation subsystem 18 processes and evaluates sensed dataaccording to the parameters of an evaluation protocol. The evaluationsubsystem 18 can detect events, using detection module 314, defined by atreatment program 300 that are related to one or more symptoms of adisorder and can use the detection module 314, and the detection ofevents may occur using a waveform analysis method as is described inU.S. Pat. No. 6,480,743 to Kirkpatrick et al. It contains a digitalsignal processing DSP module 316 for processing of the sensed data usingtemporal, spectral, and time-frequency analysis, modeling, featuredetection and quantification, and pattern matching. The DSP module 316can be used by the detection module 314 to detect selected events (andquantify selected features) such as epileptiform, tremor, or otheractivity related to various types of symptoms of the disorder beingtreated. The evaluation subsystem 18 can include compensation forvariations in heart-rhythm (e.g., heart rate may be measured by takingaverage or peak values over several measurements), activity level, bodyposition, and time of day.

When the sensor utilizes one or more sensor for measuring intracellularactivity, evaluation of sensed data can also include spike count,integrated voltage, spike histogram, envelope of activity,spike-to-burst ratio, or average spike frequency. Processing of senseddata can provide scores, an index related to measuring chaos,complexity, various Hjorth parameters, equations including weightedscores from previous results, and other types of measures and results.In one example, the analyses of the sensed data is altered by at leastone of the prior events which has been detected, or scores which hasbeen generated, which triggered an alteration in the evaluationprotocol. Evaluation of sensed data can occur in an evaluationsubsystem, can occur in a distributed fashion, as needed, by the othersubsystems of the device 10 a, and can also occur in the externalpatient programmer.

The evaluation subsystem 18 can be used to measure current therapeuticbenefit by comparing features of the current data to treatment criteria,such as threshold values for the size or number of occurrences ofelectrophysiological signatures of tremor or seizure. The evaluationoperations can be statistically based and utilize multivariateequations, logic trees, and can rely upon logical operators, to combineevaluation of different conditions used to assess the data. For example,an event may be detected“if A>X and B˜=1”, where A, B are values offeatures computed from sensed data, and X is a threshold defined in theevaluation module. Sensing and evaluation systems which may be used inthe current invention are described in U.S. Pat. No. 6,066,163, and arewell known in the art.

The treatment program 300 can use the results of the data analysis ofthe evaluation subsystem 18 to adjust the stimulation protocol 22 andselect stimulation parameter values that are used to define thestimulation signals. In some embodiments, evaluation of sensed data canentail comparing incoming signals to reference values (e.g. self-normvalues stored in the database 20) according to one or more treatmentcriteria, determining test results (e.g., positive or negative results),and modifying the stimulation protocol based upon these test results asis described in the methods herein.

Generally, evaluation of sensed data can be used to adjust therapy, orprovide closed-loop or other type of responsive treatment. Closed-loopimplementations can use sensed data of one modality to providestimulation in another modality. Evaluation of sensed electrical EEGdata may be used to select optical stimulation signals and therebyprovide“multi-modal physiological” control of stimulation parameters.The evaluation subsystem contains a detection module 314 with algorithmsfor identifying medically relevant events, which can lead to stimulationtreatment according to the therapy program of the control subsystem. Inone variation, electrographic signals are received by SEST conduits,such as electrodes, and a detection subsystem 314 includes an EEGwaveform analyzer that can implement both time and frequency analysisfor detecting characteristics of the waveforms that have been defined asrequiring adjustment or provision of stimulation (e.g., as described inU.S. Pat. No. 6,016,449 to Fischell et al. and U.S. Pat. No. 6,810,285to Pless et al., which are hereby incorporated by reference in theirentirety). Similar detection algorithms may be applied to the analysisof other types of waveforms received from other types of sensors. Inaddition to chronic stimulation, responsive cortical neurostimulationmay be a safe and effective treatment for partial epilepsy (Kossoff etal., 2004). Responsive neurostimulation can lead to less tolerance andside-effects since the stimulation is not chronic. Some have suggestedusing non-responsive neurostimulation with the addition of responsiveneurostimulation, in order to deter seizures which were not prevented bythe first type of stimulation.

In other embodiments, the treatment program 300 can control theevaluation of sensed data to provide responsive treatment to eventswhich are detected. The control subsystem 12 can operate the DSP 316module to perform signal processing and control law implementation. Atype of responsive therapy can be achieved using control-law algorithmsderived from characteristics of sensed data that provide controlsignals, as implemented by known methods (e.g. US20050240242) whichincorporate disease state estimators, proportional control laws, andother tools of control theory.

The evaluation of sensed data can entail evaluation of spatial andspatial-temporal characteristics of sensed data by thespatial/spatio-temporal (S/S-T) module 308A. When this module indicatesa specified spatial pattern of neural activation (e.g., the area oftremor activity spreads beyond a threshold value) has occurred then thismay be defined as a signature of a type of symptom for which treatmenthas been defined. By calculating the incidence of different symptoms,the treatment program 300 can calculate the relative rates of differentsymptoms and can adjust the parameters of the roving module 302 so thatstimulation with 2 or more parameter values related to the two or moresymptoms may occur proportionately. In another example, the detectionmodule may detect a type of abnormal activity at a sensor near a seizurefocus, and over time it may both increase in amplitude and also beincreasingly sensed by sensors in more distal locations (indicatingeither movement of the source or change in orientation of the dipole).This pattern of activation may be related to a specific symptom of thedisorder (i.e. a specific type, time of occurrence, duration, location,size, and count of seizure activity) and may require a uniquestimulation treatment that is provided when the activity is detectedaccording to a different spatial or spatial temporal pattern. Sinceroving of the parameters of the stimulation treatment may occur using astrategy where different values are used proportionally to the incidenceof symptoms, recognizing different symptoms by spatial-temporal profilesof one or more types of seizures (where each is considered as adifferent physiological symptom) provides essential information.

The S/S-T module 308 a may also be used when evaluating the strength ofpartial signals which are emitted by stimulators at one location andsensed by sensors at a different location. The S-ST module 308 a of thesensing subsystem, can operate in conjunction with the S/S-T module 308b module of the stimulation subsystem in order to perform testing ofvarious partial signal combinations as occurs in the method illustratedin FIG. 2 b.

The evaluation system 18 and its detection module 314 may contain aplurality of evaluation and detection capabilities, including but notlimited to analyzing measures derived from physiological conditions(such as electrophysiological parameters, temperature, blood pressure,neurochemical concentration, etc.) either jointly (e.g., electrical andoptical data are combined to assess events) or in an independent fashion(e.g., electrical and optical data are each evaluated separately toassess events) so that different symptoms of the disorder can berecognized. Different symptoms can also be defined in relation to userinput indication of different symptoms, using the communicationsubsystem 24 which communicates with the external patient programmer500.

When sensing is used in combination with stimulation, evaluation ofsensed data can lead to responsive stimulation or adjustments in ongoingstimulation. This transition can be implemented for at least one of thepartial signals, base-signals, or conventional signals that are used toprovide stimulation. Sensed data can be processed using filters, wherethe band-pass and band-stop parameters are programmable, and where thecenter frequency and filter width can be adjusted, and the filter outputcan be used to adjust the stimulation signals. Multiple filters andsignal processing routines can be used to create multiple stimulationsignals or to quickly evaluate sensed data. For example, a bank ofnarrowband filters can be used to rapidly determine a measure which isthe frequency of peak spectral power, so that this frequency can beassigned to a parameter value in order to shape the stimulationwaveform. Additionally, adaptive filters, such as Kalman filters, orindependent component analysis, can be used to track temporal orspectral characteristics of the sensed data signal. Thesecharacteristics can be used to derive a measure or a set of measureswhich are used to modify the stimulation signals. An evaluation of thesensed data can provide a measure which tracks the frequency with peakspectral power of one or more specified bands of power, such as thefrequency of a tremor or seizure.

The stimulation subsystem 14 provides stimulation according to theparameters of a stimulation protocol. The stimulation subsystem 14provides for creation and transduction of different pulses and otherwaveshapes which serve as the stimulation signals, and can includeprogrammable signal generators. The stimulation subsystem 14 includesstimulation conduits which provide stimulation signals to SEST-probes.The stimulation subsystem 14 includes modules that enable the creationof partial signals 42 a using methods such as those shown in FIG. 2 aand FIG. 5 a. The partial signal module 42 a therefore permitssubtraction of partial signals from vector (or ‘base’) signals, theaddition of interference signals, analog-based modification of vectorsignals using specialized circuits of the SC module 310, and othermethods. The provision of spatial/spatial-temporal patterns ofstimulation and sensing can be accomplished by the S/S-T module 308 a-bas may be required by different stimulation protocols unique to thedevice 10 a such as roving stimulation which may optionally beaccomplished in conjunction with partial-signal methods.

Similar to known devices, stimulation can be programmed to occur as asubstantially continuous stream of pulses, on a scheduled basis,responsively using a predefined stimulation protocol or a protocol whichis adapted based upon a characteristic (e.g., the size) of the measureddata and of the detected events (e.g., using proportional control lawswith minimum thresholds which do not output a control signal until acharacteristic of an input signal reaches a specified threshold relatedto the detection of an unwanted type of activity), and in other mannersdictated by the treatment protocol. In one variation, roving-basedtherapy may be performed by the system 14 in addition to, andindependently of, responsive therapy. Stimulation can be provided toreinforce endogenous activity and can be applied with a selected delayto be primarily in-phase or out-of-phase with a sensed feature.

The control subsystem 12, under the direction of the treatment program300, can use its communication subsystem 24 to communicate with anexternal patient programmer 500 and to implement SEST-operations usingother sensors or stimulators which may be provided by other implanteddevices, as the case may be. The communication subsystem 24 enablescommunication operations that are necessary for therapy. Thecommunication subsystem 24 may include a telemetry coil (which may besituated outside of the housing of the implantable device 10 a) enablingtransmission and reception of signals, to or from an external apparatus,via inductive coupling. The communication subsystem 24 may also includean alarm subroutine, which may cause the communication subsystem 24 tosend an alarm to the external patient programmer 500 or may send analarm to an acoustic stimulator 30 d of the device if it detects thatsomething has occurred for which an alarm should be triggered. Forexample, if the power supply 22 falls below a specified level, or iferror codes are generated by error detecting algorithms in the varioussubsystems of the device 10 a. Additional sensors or circuitry may beprovided to detect electrical shorts or fluid leaks between plugcontacts of interface connectors, and to issue an alarm if suchmalfunction occurs.

A power subsystem 22 may include a rechargeable power supply thatsupplies the voltages and currents necessary for each of the othersubsystems to function. The power subsystem may also contain circuitryfor discharging or recharging the battery (e.g., via induction) andcircuitry for indicating how much power is left, and this data can besent to the memory subsystem 20. The timing subsystem 26 suppliessubstantially all of the other subsystems with any clock and timingsignals necessary for their operation, including a real-time clocksignal to coordinate scheduled actions and the timer functionality usedby the detection subsystem 314 that is described in detail below.

While the subsystems and modules of the device 10 a are shown inspecific locations and have been described individually, they may alsobe provided in an integrated fashion. For example, the control, sensing,evaluation and stimulation subsystems may all be realized on a singlecustomized chip that has been designed to accomplish the functionsdescribed herein. Further, although the memory subsystem 20 isillustrated in FIG. 1 as a separate functional subsystem, the othersubsystems can utilize this subsystem 20 when these require variousamounts of memory to perform their operations.

A plurality of 10 a systems may also be used to perform one or morefunctions on neural tissue. Each 10 a system may be operatedindependently, or may communicate to provide synchronized stimulation,for example, as may occur when a 10 a system is implanted in the craniumof each hemisphere and delivers therapy to each, respectively. Theimplantable device 10 a may also comprise a plurality of spatiallyseparate units each performing a subset of the capabilities describedabove, some or all of which might be external devices not suitable forimplantation.

As will be described, the implanted system 10 a can be realized as anexternal transcranial magnetic stimulation (TMS) device 10 b when thecomponents are implemented in a TMS device. As an alternative treatmentto direct electrical stimulation with implanted devices, externalembodiments are also possible, for example using responsive and/orrepetitive transcranial magnetic stimulation (rTMS). Repetitive TMS hasbeen shown to decrease epilepsy with acute treatment sessions. Forexample, using treatment of 100 stimulations at 0.5 Hz, 5% below motorthreshold, twice a week for 4 weeks resulted in a 70% decrease inseizure frequency compared with the months before stimulation (Menkes etal., 2000). Other reports have also related smaller decreases, on theorder of 40%, using rTMS to treat epilepsy (Tergau et al, 1999). TherTMS treatment of various brain disorders offers advantages over directbrain stimulation in that invasive neurosurgical procedures are avoided.As in the case of continuous or repetitive stimulation, responsivestimulation, via TMS or direct deep brain electrodes, can be provided inaccordance with the methods of this invention, including adjustmentaccording to sensed activity, such as EEG rhythms. In line withdecreasing the evasiveness of therapy, the stimulation advantagesprovided by the current invention can be obtained with treatment usingdirect stimulation via implanted electrodes, rTMS, stimulation of vagalor other cranial nerve tracts, or stimulation of other tissue and organsof the human body (e.g., the stomach or heart) which may be useful inproviding treatment to various disorders.

FIG. 2A shows a schematic representation of a system designed to createand apply partial signals during stimulation. This system can berealized by the stimulation subsystem 14 and SEST-interface 44 a. Asignal creator 40 works with a partial signal creator 42 in order tocreate the partial signals, which are then routed 44 to be provided toselected contacts of stimulation conduits 32. The stimulation conduitsare located sufficiently close to enable at least the partial summationof the individual fields of the partial signals, in order toapproximately create a vector signal in at least a portion of a neuraltarget. In one method the signal creator 40 supplies a base signal to apartial signal creator 42, which modifies the signal to create a numberof partial signals. For example, by adding selected interference signalsto the base signal, partial signals can be created so that theirsummation leads to a vector field which is approximately the basesignal. The size and polarity, and even orientation, of the interferenceand partial signals can be adjusted, by the partial signal creator 42,based upon an algorithm which incorporates the spatial location,impedance, and orientation characteristics of the stimulation conduits(e.g., electrode contacts or optical outputs). The partial signals canbe generated digitally using algorithms, or analog circuitry, or can beselected from a database 28 of predefined partial signals. Partialsignal generation may also include information about the 3-dimensionalpositions of grounds and active leads as well as the approximateimpedances, orientation (in the case of directional leads) and otherrelevant characteristics of the leads, which is stored in the database28. The creator 42 can generate at least two partial stimulation signalsbased upon these calculations in order to produce approximately thedesired electrical field summation signal in approximately one or moretarget tissue regions.

The partial signals may be directed to their intended stimulationconduits 32 by the signal router 44, which also may be realized withinthe stimulation subsystem 14 and which can contain SC components such asdigital-to-analog converters, filters, amplifiers, switches, chargebalancing and biasing circuits, and mutliplexors, each of which can beseparate components or which can be embodied into a specializedmicrochip.

FIG. 2B shows a schematic representation of a method of using a systemof the invention, such as that of FIG. 2A, that is designed to createpartial signals. The first step is to create at least one stimulationsignal 50 to be used during treatment. The stimulation base signal(e.g., a signal that has been selected due to its ability to provide abenefit such as symptom relief) is then transformed into two or morepartial signals 52 which are provided at each of two or more contacts54. A calibration method (including steps 54, 56, 58) can be used, fromtime to time, in which the partial signals are adjusted based upon datawhich is sensed concurrent with stimulation. For example, a calibrationsignal which may be at least one partial signal is used to stimulatecontact set“i” of N contacts 54, and data are sensed at contact set“j”56, where sets“i” and“j” each include at least one contact. The senseddata allows empirical measurement of the electrical field and can beused to adjust the partial signals 58 so that the actual field vectormore closely approximates the intended vector field in 3-deminsionalspace.

FIG. 3A Shows a generic implantable stimulation device 10 that has astimulation conduit which includes five electrical contacts (32A-E) thatare implanted in the neural tissue 36 of a patient 38 (not shown). Theimplantable stimulator 10 contains sensing, control, signal generatingand computational circuitry, a power supply, sensors and othercomponents which are commonly found generically in implantablestimulators such as have been described in U.S. Pat. No. 6,066,163,US2002/0072770, & US2004/017089. The stimulator 10 may also be realizedusing the neurostimulators 10 a and 10 bshown in FIGS. 1 and 15. Thestimulator device 10 can contain a general access port 6 which servesdifferent functions in different embodiments. For example, the accessport 6 can comprise a re-sealable septum which accepts a needle forreplenishing fluids used in drug delivery, or the access port 6 canaccept a control link from an external controller device 500. The device10 can also contain a connection port 8 for connecting, for instance, tosensors 34 which can provide sensed data, or which can accept a signalfrom another implanted device for permitting two or more devices tocollaboratively provide treatment.

In some of the described methods, stimulation parameter values relatingto characteristics such as modulation rate are described as alternatingor roving. This may occur independently for each of the one or more(partial) signals of each of the stimulation conduits 32. Accordingly, afirst stimulation signal could rove from 20 to 25 Hz, while a secondsignal concurrently roves from 26 to 27 Hz. The temporal delay, phase,amplitude, or other characteristics of the stimulation signals at eachelectrode can be independently set in the stimulation subsystem 14. Thespecified delay, amplification, filtering, and other parameters used toadjust stimulation signals according to sensed data can occur accordingto treatment protocols and, in selective embodiments, can occurresponsively or according to the implementation of one or more controllaws.

Stimulation can occur using two or more stimulation lead contacts (e.g.,32A and 32B) which stimulate at levels that would be subthreshold ifprovided individually, but which combine to produce super-thresholdstimulation. Subthreshold stimulation can be used with stimulation leadswhose fields summate to the extent needed for clinical efficacy (i.e.the fields of the partial signals combine to produce super-thresholdcharacteristics) primarily in the region where neurostimulation isdesired. In this example, contact 32A (black region) produces a field(grey region) that overlaps with the field produced by contact 32B, bothof which produce fields as current travels to contact 32C, such thatvector fields occur in target area 1 (‘T1’). Bipolar contacts 32D and32E may each be used to stimulate with a partial signal so that theoverlap of their fields causes vector summation to stimulate target area2 (‘T2’). If an area of tissue is adjacent to a contact 32E, but is anon-target (‘NT”) area which produces side-effects when inadvertentlystimulated, then even if the field produced by contact 32E shouldstimulate this non-target area, inadvertent stimulation of thenon-target area may not lead to side-effects since the characteristicsof the partial fields are different than those of the vector field(i.e., since the partial signals have a different spectral content thenthe vector field). FIG. 3B shows 2 sets of SEST-probes 31 e and 31 e′which contain sets of contacts located bilaterally and which may bealigned along the spinal cord of a patient when partial signals are tobe used during treatment.

FIG. 4 a shows examples of partial signals. Each signal is part of a setwhich can be provided at 2 or more different lead contacts. Each“set ofpartial signals” will combine to form a desired signal (a vector sum ofthe two partial signals) in or near the target tissue while stimulatingwith the partial signals outside of the target region. In row A, awideband noise signal is shown in column 1, labeled“Signal #1”, whichwhen added to the“Signal #2” of column 2 will result in the“combinedsignal” shown in column 3. Rows B-E show other partial signals sets andtheir vector summation fields. The described methods for choosingstimulation parameters for conventional stimulation signals can also beapplied to the selection of partial and vector signals. If a ‘basesignal’ is selected as the combined signals of rows A-D (which areidentical), each of the sets of partial signals can be tested, and theones which produce therapy and reduced side effects can becomesuccessful stimulation signals. Only base signals and partial signalswhich are found to be successful stimulation signals may be selected tobe included in the set of candidate stimulation signals which can besubsequently used during treatment.

In FIG. 4B, additional examples of partial signals are shown havingunique characteristics relative to the those of the vector signals ofcolumn 3, and offer advantages over known stimulation signals. In thefirst row of FIG. 4B, two saw-tooth pulses serve as the partial signalsand these combine into a vector signal which is a square wave at thesame frequency, having pulses of longer duration and different shapethan the partials. Both the duration and shape of the partial signalscan thus differ significantly from the resulting combined signals.Additional pulsatile signals are shown in rows G-l. In these cases,partial signal 1 was subtracted from the combined signal in order toobtain partial signal 2, as may occur in the partial signal creator 42or related methods, e.g., steps 52, 82, 92. Among the variousadvantages, the signals in Row G combine to provide a vector signalwhich is faster than the partials, Row H combines single polaritywaveshapes to create a bipolar vector waveshape, and Row I results in apulse train of rate 2N, where the partials are each set to N, due to thephase relationship of the signals.

Partial signals which are applied to the non-target region can beselected as those which are unlikely to stimulate that area in unwantedmanner. A sufficiently fast carrier frequency may affect neural tissueonly at the onset of a train because it exceeds the chronaxie of thetissue and is thus functionally“invisible”. In contrast, various rangesof high frequency stimulation (e.g., 1-6 kHz range) can both excite orblock neural activity (Tai et al 2005). Modulation of a carrier signalwhich freezes, inhibits or excites a neural target can be useful inproviding very specific entrainment, because this will oscillate withthe modulation envelope (e.g., with the amplitude or frequencymodulation). Additionally, when using a pulse train, pulse shape and/orduration can be set, relative to its current, voltage,inter-pulse-interval, or frequency so that the partial fields fail toentrain, or produce side-effects in the NT area, while the vector fieldcontains pulses that are entraining (e.g., FIG. 4B).

Stimulation signals can be provided to both mono-polar and bi-polarstimulation conduits. When generated by mono-polar leads, these maystimulate as cathode or anode and may supply stimulation in conjunctionwith a further lead that, for example, serves as ground. Each electricalcontact may be a ground, isolated, mono-polar or bi-polar with respectto anode/cathode assignment. When operated in a bipolar mode, one of thelead contacts can serve as a ground or opposite polarity relative to theother contact. Alternatively, the housing of the stimulator 10 can serveas anode, cathode, ground or may be floating. Other combinations ofpolarities are possible as well, for example the shell of the stimulator10 can be divided into different sections which are electricallyisolated from each other, and when more than one stimulator 10 is used,each may have a shell with a different electrical function, as may occurwhen the methods are implemented in stimulators such as the BION™, or aBION™ network. When multiple stimulators are used to provide the partialsignals, these may have their grounds and power-sources connected toprovide a common ground or power-source, although these may also beelectrically independent.

Partial signals can also be created by the method illustrated in FIG.5A, and comprises the step of creating a low frequency base signal 60which is intended as the vector field signal, created by the summationof the partial signals in approximately the target tissue. The lowfrequency signal is added to a 1 ^(st) interference signal 62 a tocreate a first partial signal, and then added to a 2^(nd) interferencesignal to create a second partial signal 62 b, and this process iscontinued until all the partial signals are created. The partial signalsare then each applied to a selected contact 74. Step 74 can occurcontinuously, repeatedly, responsively, or according to alternatestrategy as dictated by the treatment program. The partial signals canbe re-assigned to the same or different contacts in subsequentiterations, after appropriate modification for electrode geometry,impedance, etc. Additionally, as indicated by the arrow from step 74 tostep 60, this process can be repeated if the low frequency base signalor the partial signals require replacement, for example, as dictated bythe treatment program 300. In FIG. 5B, a method is shown where a basesignal with high frequency spectral content (e.g., a pulse train,paired-stimulus waveform, or arbitrary waveform) is created 76, and theinterference signals are added to this signal 78 a, 78 b, to createpartial signals that are applied at the contacts 74. A further method ofproviding the partial signals is shown in FIG. 6. The first step is tocreate a base stimulation signal 80, then create 2 or more partialsignals 82 a, 82 b by modifying the base signal. Partial signals can becreated by distributing the base signal spatially and/or temporally(possibly having some durations of overlap) across the differentcontacts, and then applying each partial signal to a unique contact 74.As the figure shows, the steps 80, 82 and 74 can be repeated in a loopto provide adjustment of the partial signals and/or base stimulationsignal. If the stimulation signal is to remain constant and only thepartial signals are to be adjusted then only steps 82 a, 82 b and 74need be accomplished. All three steps can occur approximatelysimultaneously and continuously. After a specified amount of time haselapsed 26 the contacts for the first and second partial signals may beswitched (e.g., step 84 of FIG. 6). In one embodiment, after a specifiedduration, the signals used at lead contact 1 become signals for leadcontact 2, and vice-versa.

When the stimulator 10 is an external TMS device, instead of contactsthe stimulation is produced by TMS coils which induce magnetic fields inthe brain, and the re-assignment of partial signals may be even moreimportant: unlike implanted electrodes, the fields will alter theactivity of significantly larger portions of tissue outside of thetarget area. When more than 2 partial signals are needed, steps 82 a and82 b, for example, are extended to steps 82 c, 82 d, etc to create theseadditional signals.

In a further embodiment, the creation of partial signals can occur byprocessing the base signals according to an algorithm. As is shown inFIG. 14, the stimulation signals can be created 90 and then these basesignals can be processed 92, for example, by algorithms or processesimplemented digitally or in analog form, in order to produce modifiedpartial signals 94. The process can utilize a filtering algorithm whichcan iteratively filter the stimulation signals with different band-passfilters in order to create unique, and even spectrally orthogonal,partial signals which will combine to approximate the base signal.

Stimulation with Modulated Carrier Signals.

There are several“technical” problems which are encountered whenproviding neurostimulation, in the treatment of a disorder. Regardlessof whether the stimulation signal is one of low or high spectralcontent, the signals which provide the best therapy, may not be optimalwith respect to stimulation of issue. While certain stimulus waveformsmay be good for treatment, these may be less well suited fortransmitting energy from the electrodes to tissue, and subsequentlythrough tissue itself. An approach to optimizing the desired effects ofstimulation is to construct a“carrier signal” which may be comprised ofan oscillating carrier at some high frequency, Fc(H), which is modulatedby some lower frequency Mf(L) or contour Mc(L). In a preferredembodiment, the contour of the modulation waveform itself may bedetermined by sensed data, and/or may be a sine wave, pulse pattern,ramps of a specified rate of change of amplitude, or any arbitrarywaveform. Changing the Fc while maintaining a constant modulationfunction may increase energy transmission, entrainment or selectiveentrainment of a neural target. These methods permit increasedstimulation efficacy, by tailoring the Fc and Mf characteristics. Moregenerally, a first characteristic of the signal is selected to providetherapy, and a second component of the signal is adjusted and providedin order to provide a secondary benefit such as decreasing a side effector increasing energy transmission.

In some situations, it is advantageous to adjust the modulation envelopewhile the carrier signal (which may be a frequency, or band-pass noise,pulse train, etc) is maintained. In other situations, the modulationfunction should be held constant while the carrier signal is maintained.Alternatively, both may be adjusted in order to provide a therapeuticbenefit such as better entrainment of tissue. In one method, a firstcharacteristic of the stimulation signal such as a modulation rate maybe selected based upon a first therapeutic benefit such as symptomrelief, and is then held constant. A second characteristic of thesignal, such as the carrier signal may then be roved, adjusted, oralternated in order to provide a secondary advantage, for example,increase the transmission of the signal through tissue (possibly thenpermitting a signal with decreased current or voltage to be used),decrease side-effects, or increase the level of entrainment of thestimulated tissue. The sensed data may be used it to determine carrier,envelope, or modulation rate of the stimulation signal, while adifferent characteristic of the signal is adapted to provide improvedtherapy.

For all the types of stimulation signals which are described in thisspecification, the stimulation signal can be provided with, or spectralcontent can be assessed, using the signals as described or using theirfully or partially rectified counterparts. It should also be noted thata non-rectified amplitude modulated signal, does not have energy at therate of modulation. The spectral energy of a modulated signal occurs atdifferent frequencies depending upon the carrier signal. For example, anamplitude modulated signal has energy at the carrier frequency (C_(f))and at sideband harmonics which occur at C_(f)+/−the modulation rate(M_(f)). Only by rectifying a signal will spectral energy appear at thefrequencies of the modulation envelope. Generally, the neurons in thetarget tissue will become entrained by the modulation envelope, whilethe different carriers which may be used will act to entrain differentneuronal populations and to transfer the modulated signal with differentamounts or degrees of efficiency. Accordingly, the spectral content ofthe rectified energy of the stimulation signal may better reflect thespectral content of the evoked activity. In one embodiment, signalshaving rectified spectral content of between 0.5 and 20 Hz are used,although the signals themselves are centered around zero to avoid issuesrelated to the application of D.C. and non-balanced stimulation signals.

The width of the spectral content of the stimulation signal may also bea parameter that is adjusted. Modulation of neural tissue using anarrow-band (e.g. 5 Hz) stimulation signal rather than a pure carrierwave (or pulse train) may entrain a greater proportion of neurons, wherethe width of the band-pass is adjusted to provide maximum entrainment.Additionally, in order to increase therapeutic efficacy, the stimulationsignal may not return to, or cross zero, on every cycle, but rather canbe biased. The second characteristic can be related to adjusting for aspecified and desired level of positive or negative DC shift.

Generation of stimulation signals form sensed data can rely upon one ormore fixed or programmable band-pass filters. The sensed data can beprocessed in several manners, and each of these processes can be used todetermine a specific characteristic of the stimulation signal. Whensensed activity is evaluated for a tightly bound neuronal oscillation,the band-pass of the filter may be set to be relatively restricted (e.g.0.5 Hz bandpass). The output signal, which may be based upon a filteredform of the input signal, may be generated utilizing an additionalnarrow-band filter to obtain measure which is an estimate of thefrequency of peak spectral power, while a larger band-pass may provide acarrier signal which is more efficient in entraining a neuronal target.The peak frequency estimate can serve to create the envelope by whichthe carrier signal is modulated. The neural target may contain neuronswith a range of natural frequencies that vary somewhat from the centraltendency, causing periodic shifts in the peak frequency of spectralpower (e.g., alpha rhythm) and consequently shifts in the modulationenvelope of the stimulation signal. Alternatively, the stimulationsignal may be a band-pass signal generated with or without sensed data.An arbitrary carrier waveform of specified spectral content can becreated by using a random noise generator and then filtering this signalwith filter settings selected in order to provide the desired carrier.The stimulation signal may be a selected band encompassing energylimited by a first frequency and a second frequency. In one example, theband-pass signal is chosen so that the band contains spectral contentwhich lies primarily somewhere between at least approximately 0.5 Hz andat most approximately 20 Hz. The width and center frequency of the bandcan be periodically selected to provide measurement of a particular typeof basal or evoked activity which is related to a symptom of thedisorder. Although altering the signal characteristics of thestimulation signals based upon characteristics of the sensed data may beimplemented in a manner that will cause the stimulation signal toalternate its characteristics over time, this does not occur in a strictmanner. In other words, using characteristics of current sensed data todetermine a stimulation signal will not necessarily be related to thecharacteristics of different symptoms such as their incidence, nor is itgeared towards treatment of multiple symptoms of a disorder.

Roving Based Stimulation Strategies.

The device 10 a can also provide therapy by stimulating at severaltherapeutic frequencies, rather than stimulating at a single particularfrequency. For instance, stimulation can occur using a signal whichcomprises a consistently or periodically roving signal. The parametersof the signal may be defined to rove within a selected range, or acrosscertain values, that have been found to produce therapeutic results. Inone embodiment different values used in the roving therapy are relatedto the treatment of different symptoms of the disorder. Further, theroving may be adjusted so that it occurs according to the proportionalincidence of different symptoms. In FIG. 7, step 200 can includecreating a signal that roves over time. This signal is then subsequentlyapplied during stimulation treatment 202. The method can also encompassperiodically creating a new roving signal (returning arrow) and applyingthis 202. The steps of FIG. 7 can be done for one electrode contact, forall electrode contacts, and uniquely for all electrode conduits, and mayinclude sequential activation of SEST-probes 31.

The roving of a parameter of stimulation protocol can be used to adjustthe stimulation parameter values of a wide number of signals, such asthe range, center frequency, rate of modulation, or depth of modulation,of: a frequency modulated carrier; a linear or logarithmic chirpwaveform; dynamically adjusted band-pass noise, where the band-pass ischanged over time. Roving may be used to adjust the parameter values ofpulse type signals where a parameter such as duty-cycle is roved overtime. The resulting stimulation signals therefore do not have a singlefrequency or rate of stimulation, but rather alternate between or roveacross a range of therapeutic frequencies. These signals can havespectral and temporal profiles which are dynamic and temporallydistributed. The signals may contain different spectral content atdifferent moments of time, and energy from one or more spectral bands atparticular moments in time. The stimulation signal may be comprised ofenergy that spans across a range of therapeutic frequencies (e.g., itmay rove between 1 and 18 Hz), and may contain spectral energy of whichonly a portion spans a therapeutic frequency range (e.g., 30% of theenergy is between 1 and 18 Hz). All of these roving parameter values canbe adjusted with respect the characteristics of one or more symptoms offeatures of the sensed data.

Roving signal protocols offer a number of additional advantages. Forexample, a particular frequency (e.g. 3 Hz) may not always be theoptimum rate of stimulation. A particular spectral profile can serve toprovide better therapy than others, due to such factors as changes inbrain state. Such changes can be reflected by changes in the spectralcontent, or other measures of endogenous activity. When sensed data arenot evaluated slowly roving the a parameter can still offer advantagesover merely using a specific stimulation signal since it can modulate agreater assortment of neurons, during different brain states and indifferent manners. In the case of epilepsy, periodically or responsivelyalternating the spectral content using parameter values that have shownto produce good test results may deter a wider assortment of unwantedsymptoms.

Roving the stimulation signal may also decrease the interference ofstimulation with endogenous processes. For example, studies have shownthat when low frequency stimulation, such as 3 Hz, is used in animals,that learning and attention may be impaired, while a repetition rate of10 Hz or so does not lead to such impairment (John et al, 1961; Bawin etal 1973). Although many current stimulation methods use stimulationsignals which are considerably faster, the incorporation of lowerfrequency signals should address this type of issue. The power andfrequency of the alpha and theta rhythms have been shown to be relatedto perceptual framing, neural timing operations, and memory capacity andLTP (e.g., Huang & Kandel, 2005; Hwang et al, 2005; Varela et al, 1981)and stimulation which alters these rhythms on a long-lasting basis mayresult in disruption of the cognitive correlates. The magnitude of theseside-effects may be subtle or moderate and can be measured bycognitive-behavioral testing or by neuroimaging/neurophysiologicaltests, including evoked potential testing, which may be used to guidethe therapy program. In any case, chronic 3 Hz stimulation may causememory, perception, or learning problems patients while a roving carriercan be used to minimize these unwanted effects. Additionally, while 10Hz may be less effective in reducing or preventing the emergence ofseizures than, for example, 3 Hz, it may work sufficiently well to actas a temporary substitute (as dictated by the roving protocol) so that 3Hz stimulation does not continuously occur when it is interfering withendogenous brain processes. Since the two frequencies of stimulation maybe able to block different types of seizures, roving the frequency ofthe stimulation signal would be better than using either signal alone.In other words the two parameter values defined for roving of thestimulation signal can be directed towards providing therapy to twodifferent symptoms, which is a central advantage of the invention. Whenthe function which guides the roving of a parameter value isdiscontinuous, the roving will be identical to alternating.

Selection of Roving Parameter Values and Multi-Protocol TreatmentPrograms.

The selection of two or more different stimulation parameter values maybe done based upon sensed data obtained during therapy or prior tostimulation, during an initial evaluation period. The two or morestimulation signals can be chosen order to reduce the likelihood of twoor more symptoms (e.g., in epilepsy treatment, two or more stimulationsignals can be chosen order to reduce the likelihood of two or moreseizure types developing in the brain).

In one illustrative embodiment, alternating between two rates (e.g., 3and 5 Hz) is adjusted according to treatment of different symptoms. Forexample, a 3 Hz stimulation signal might be found to block 95% ofseizures, while 4 Hz stimulation is found to block 1% of seizures, 5 Hzstimulation blocks 5% of seizures, and 6 Hz blocks 60% of seizures. Ifonly one stimulation signal was to be used for basal stimulation then a3 Hz stimulation signal would likely be selected. If two stimulationsignals were chosen, these might be the 3 Hz and 6 Hz signals. However,the 5 Hz stimulation signal can prevent a different type of seizure thanthat blocked by 3 Hz and 6 Hz. Thus, alternating between 3 Hz and 5 Hzmight be therapeutic than simply stimulating at 3 Hz, or 3 Hz and 6 Hz,since the two signals chosen provide therapy to two different symptomsof the disorder. Additionally, the stimulation signals can be providedin proportion to the incidence of seizures to which they are related.For example, if seizures blocked by 3 Hz occur 70% of the time, whileseizures blocked by 5 Hz occur 30% of the time, then the stimulationsignal may stimulate at either 3 or 5 Hz (or 140 and 180 Hz) forcorresponding proportions of time or incidence (e.g., the method FIG. 8using only steps 212 and 214).

If a first parameter value is useful for blocking a first category ofseizure, and a second parameter value is more akin to blocking a secondtype of seizure, then determining the stimulation protocol using senseddata may occur using a number of strategies. A “historical strategy” maybe particularly used when seizure prediction from sensed data is notvery accurate. Historical strategies tailor the stimulation protocolbased upon the number of past events which were detected over priorperiod. As is shown in FIG. 8, data are sensed 210 for a period whichmay be several days or weeks or longer, the sensed data are evaluated tomeasure the number of occurrences of one or more seizures over aselected period of time 212. The stimulation parameter values are thencreated for signals which are likely to block each seizure type 214, andthese are then implemented by the roving stimulation protocol. Theprotocol can be designed based upon the proportion of different seizuretypes that were detected 216. This protocol is then used to providestimulation 218. When prediction of seizures is more accurate, thenumber of responsive interventions for each seizure type, rather thanseizures themselves, may be used.

Rather than stimulating with two types of signals, each of which isdesigned to treat a symptom, for example, desynchronize activity andprevent seizures, the different stimulation parameter values can bedesigned to treat a particular symptom in two manners. For instance afirst stimulation protocol can use parameter values which have beenfound to modulate a particular level of neurotransmitter in regionswhich have been shown to decrease seizure emergence, while a secondprotocol can use parameter values which are found to block the emergenceof activity which anticipates seizure emergence, for example, slow waveactivity. The level of neurotransmitters in a region relevant to thesymptoms of a disorder can be considered part of the brain's state. Theselection and alternation of signals can be done (with or without senseddata) to maintain a brain state or neural state, by applying stimulationso that this state is controlled to remain within a normal range, acontrol range which may be user defined, outside of a critical range.The neural state is controlled to generally deter the likelihood ofcertain neurological signs or symptoms or precursors to these symptomswhich may, for example, be abnormal patterns of activity (or patterns ofcoherence, synchrony, or disentrainment) related to EEG, neurochemistry,or bloodflow. Abnormal synchrony may be reflected in the sensed data bya number of measures. In the case of EEG, for example, coherence orsynchrony measures may be obtained from two or more sensors, or a changein the spectral content obtained from one or more sensors, such as anincrease in (or amalgamation of) power over a limited frequency rangeassociated with a tremor or seizure symptom. Using non-linear measures,estimates of chaos, system-state, complexity, and other estimates may beused to provide measures of synchrony. The selection and alternation ofsignals can be done with sensed data to maintain or deter a brain state,neural state, symptom, or abnormal measure. The selection andimplementation of parameters to accomplish this may occur using one ormore algorithms or control laws which maintain a neural state or sensedparameter within a particular range with reference to reference state orvalue (e.g.,U.S. Pat. Nos. 6,463,328; 6,366,81 3).

Further Considerations Concerning Endogenous Activity.

Commonly used therapeutic stimulation parameters for DBS (e.g.,monopolar cathodic; 1 to 5 V stimulus amplitude; 60 to 200 μs stimuluspulse duration; 120 to 180 Hz stimulus frequency) have been derivedprimarily by trial and error. In some treatment applications, theparameters have been determined to be effective because of the nearlyimmediate effects of DBS for treatment of disorders such as movementdisorders (e.g., tremor and Parkinsonian motor symptoms). The delaybetween initiating therapy with a set of stimulation parameters and theamelioration of symptoms, such as decrease of depression, may have adelayed time-course, as is often seen when treating these disorders withvarious pharmaceuticals. The successful stimulation parameters for thetreatment of psychiatric diseases and more complex disorders cantherefore be considerably more difficult to derive. Further, asdiscussed, there may be different mechanisms behind slightly differentsymptoms of a disorder, which require different treatments, and furtherconsiderable heterogeneity of symptom clusters which are uniformlyclassified as a particular disorder. Strategies which assist inselecting or applying stimulation which has an increased chance of beingtherapeutic, may become increasingly important for these more complexdisorders. Successful treatment for a wide array of disorders may dependupon treating multiple symptom abnormalities, and will demand a morethoughtful consideration of the separate advantages of different typesof stimulation methods.

Epilepsy may arise from the imbalance of excitatory and inhibitoryprocesses. Enhancement of the activity of brain inhibitory mechanisms,mediated through chronic stimulation, has been shown to lead to abeneficial therapeutic effect for some intractable epilepsy patients.Since lower frequency endogenous potentials, e.g., 0.1 Hz to 10 Hz, arethought to reflect inhibitory processes, low frequency neurostimulationmay increase inhibitory processes and decrease the emergence ofseizures. Indeed, low frequency stimulation has been shown to provideanti-epileptogenic benefit (e.g., Velisek et al, 1986, D'Arcangelo etal, 2005; Misawa et al. 2005;Weiss et al, 1995). However, as noted, thepicture is more complex since both low and high frequency chronicstimulation can decrease the occurrence of seizures. A model based uponan imbalance (generally up-regulation) of cortical excitability thusdoes not seem to be a simple story, since both low and high frequencystimulation can provide therapeutic benefit. In a pertinent illustrativeexample, Chkhenkeli et al, (2004), studied the inhibitory effects ofchronic electrical stimulation in 150 patients with implantedintracerebral electrodes, with respect to neocortical and temporal lobemesiobasal epileptic foci. Stimulation was provided to a number ofstructures including the head of the caudate nucleus (HCN), cerebellardentate nucleus (CDN), and thalamic centromedian nucleus (CM). Resultsdemonstrated that both 4-8 Hz HCN and 50-100 Hz CDN stimulationsuppressed the subclinical epileptic discharges and reduced thefrequency of generalized, complex partial, and secondary generalizedseizures. Additionally, CM stimulation (20-130 Hz) desynchronized theEEG and suppressed partial motor seizures. It was also found that directsubthreshold 1-3 Hz stimulation of the epileptic focus could suppressrhythmic after-discharges. In this study, seizures were eliminated orgreatly attenuated for 91% of the patients: chronic neurostimulation maygenerally suppress the activity of epileptic foci, and, in long run,stabilize the regions displaying epileptic foci activity. However, thespectral content of the signals that provided therapy varied greatly, inpart as a function of location. Although direct brain stimulation, mightserve as a useful tool in the treatment of intractable and multi-focalepilepsy, both low (e.g., 1 Hz) and high (e.g., 50 Hz) electricalstimulation have been shown to decrease or prevent seizures (e.g.,Kinoshita et al, 2004). It is normally difficult to ascertain, even withextensive testing of the patient, which parameters may be mosteffective.

Roving between different stimulation parameter values is obviously onemanner of addressing the treatment of different symptoms, or addressingthe treatment of a particular symptom that may be treated in more thanone manner (e.g. as can be varied due to changes in neural state whichare only partially related to the disorder). However, when choosingparameter values which may be therapeutically beneficial, it is notalways possible to determine how well various parameter values willserve to deter one or more symptoms. For example, a seizure may occuronly once in several weeks or months and comparison between differentstimulation signals in deterring the seizure may take years. Rather thanevaluating how well different stimulation signals prevent or detersymptoms, stimulation parameters can be set or“prescribed” based uponthe characteristics of endogenous rhythms of brain activity. Theseendogenous rhythms may, or may not, contain activity reflective of theevents themselves. For example, peak frequency of beta power may be usedrather than examining a characteristic of epileptiform activity itself.In one method of treatment, neurostimulation parameter values may beselected to create stimulation signals that match, mimic, or efficientlydrive/disrupt, the endogenous rhythms of the neural targets. Rather thanusing arbitrary stimulation signals (e.g. 180 Hz pulse trains) which arelargely above the frequencies of endogenous activity currently known toupregulate/downregulate activity when stimulation modulates neuraltissue at slow rates, it may be adjusted as a function of these rates. A10 Hz stimulation signal may be adjusted to 9 Hz if the patient's alpharhythm shows a dominant peak at this lower frequency, since the brain islikely become more entrained as the stimulation pattern approximates(and drives) the brain at its naturally occurring rates. The stimulationparameter values which are selected may crate signals which arecomprised of either low or high frequencies in different regions, andmay be inhibitory, excitatory, synchronizing, or desynchronizing, inrelation to the endogenous activity. Varying neurostimulation parametervalues such as frequency, stimulation onset, or size of the stimulationsignal, in relation to endogenously occurring EEG rhythms, in order toenhance or attenuate these rhythms, should improve the benefit ofroving-based therapy, especially stimulation signals contain lowerspectral power.

In contrast, regardless of the stimulation signal used, and thetherapeutic benefit of either low or high frequency stimulation may bedecreased and the emergence of unwanted and unpleasant side-effects mayincreased when the stimulation signals are too close to the normallyoccurring rhythms, due to interference with normal brain or cognitivefunctions. Therefore it may be better, in treatment of certaindisorders, to avoid using stimulation parameter values that createsignals which are too similar to endogenously occurring rhythms. Theissue of unwanted side-effects related to cognitive interference,memory, and perceptual processes, has not been considered much by recentneurostimulation protocols. This issue may be highly relevant when usinglow frequency stimulation. For example, low frequency endogenouspotentials have been shown to be intrinsic to both conditioning andhigher order learning (John et al, 1961). Low frequency stimulation (orvery high frequency stimulation pulses modulated at slow rates) whichdrives endogenous activity has been shown to both increase thedevelopment of conditioning to a stimulus, and decrease the subsequentextinction of the response during non-reinforced trials (Holt & Gray1985; Bawin, et al, 1973). Alternatively, low frequency stimulationwhich occurs at different frequencies than those which occurendogenously, or which disrupts the endogenous low frequency rhythms,has been shown to have little effect, or to slightly impede learning.John et al (1961) examined using low frequency stimulation by using a100cycles per second (CPS) biphasic pulse carrier, which was modulatedat low rates of either 4 or 10 CPS, and found that the 4 Hz modulationwas much more inhibitory than 10 CPS and led to decreased conditioningin some animals. Accordingly, while chronic or semi-periodic stimulationof various brain regions can be used to decrease the presence ofunwanted activity such as seizures, it may also cause unwantedside-effects such as interference in attention or learning. By rovingthe neurostimulation parameters so that the stimulation frequency is notheld constant, the effects of this neurostimulation on factors such aslearning and attention may be decreased, while the therapeutic efficacyof the stimulation persists.

Additionally, studies have shown that neurostimulation is able toincrease the intrinsic firing of low frequency endogenous potentials,when the neurostimulation frequency is matched with the internalfrequency, while when the neurostimulation frequency is different fromthe internal frequency in a similar range, the neurostimulation may actto block this activity or lead to an augmentation of activity in adifferent frequency range (which may not be within the same frequencyrange as the neurostimulation signal). In one embodiment, endogenousbrain activity can be reinforced by neurostimulation using a methodwhere data are sensed from a sensor, and the sensed data are processed(e.g., amplified) and becomes a signal which sent to a filter, thefilter having a band-pass that has a center frequency which is intendedas the neurostimulation frequency, and wherein the output of the filteris used as a neurostimulation signal at one or more leads. The centerfrequency of the filter can be determined by the dominant peak frequencyof the endogenously occurring activity, and the neurostimulation can betriggered when the output of the filter is above or below a specifiedlevel, or can be provided responsively based upon a different strategy.Accordingly, if synchronized activity was sensed from a target region,this signal could be used to create a stimulation signal that could befed back to one or more stimulation electrodes either in phase, out ofphase, or with a specific time delay (each of which may be individuallyset for each electrode contact) in order to reinforce, disrupt, oradjust the endogenous activity. Further, since the dominant frequenciesof the internal rhythms can reflect the envelope of the populationactivity, and the likelihood that a cell will fire is somewhat dependentupon the pharmacological and electrical characteristics of theextracellular space, the electrical stimulation can have differentialeffects when introduced at different states of the internal rhythm. Inother words, the same signal can have different effects when introducedin different neurophysiological“states”. The stimulation signals can beadjusted to occur at different lags in relation to the endogenousactivity in order to increase the influence of stimulation.

The stimulation signal that is applied can have a spectral/temporalcontent which is set (to be a different from the endogenous frequency)in order to entrain the population at a spectral frequency that is notrelated to unwanted symptoms of a disorder This method could be used totreat disorders such as pain, tremor, epilepsy (seizures), depression,or other disorders where behavioral symptoms are associated with inincrease in synchronized firing of a brain region in a particularfrequency. In the first step, a band-pass of the filter can beprogrammed using bands relied upon by conventional quantitative-EEG. Ifa signal with a peak frequency between 4 and 8 Hz is desired then thecenter frequency of the band-pass can be determined by, or set tomeasure, the peak frequency in the EEG in that range (theta range),while a roughly 10 Hz stimulation signal is desired then the centerfrequency of the band-pass can be determined by, or set to measure, thepeak frequency in the 8 to 12 Hz range (alpha frequency). The dominantfrequency of the stimulation signal can be set to be 1 or 2 Hz above thepeak frequency detected within the selected band. In other words, bydriving the brain at a frequency which is one or two Hz away from thedominant frequency of a tremor, the tremor may be attenuated.

When the neurostimulation signal is modulated at, or promotesentrainment at, frequencies which are different than the endogenous EEGpatterns, the neurostimulation will attenuate the endogenous activityand promote activity at other frequencies, even though these may bedifferent than the stimulation frequency (Bawin et al, 1973). While theissue, of matching endogenous brain activity in order to enhanceentrainment and modulation effects, should be addressed when providingtherapy for a wide array of disorders, this may be especially importantfor brain stimulation. While only certain portions of the brain followfrequencies above 80 Hz, both cortical and sub-cortical structuresnaturally produce rhythms at these rates, such as the conventional QEEGrhythms which are approximately, delta (0-4 Hz), theta (4-8 Hz), alpha(8-12 Hz), beta (12-18 Hz) rhythms and the famous 40-70 Hz gamma-bandresponse which is related to binding of multi-modal stimulus features,and the formation of percepts. Alternatively, other the EEG can beevaluated using different bands of spectral energy. Additionally,event-related components such as the N100, P300, N400 and numerous wellknown components have spectral components between 1 and 200 Hz, andstimulation of structures involved in these responses at frequencieswhich they use functionally, may cause disruptions in brain processes,such as those related to sensory evaluation.

Methods and systems for improving treatment by incorporating measures ofthe sensed endogenous rhythms of the brain or body can be relativelysimply adapted (e.g. FIG. 11). A filter can be used having a band-pass(for example, the 4-8 Hz range) which allows the activity of a specificstructure, such as the hippocampus, to be sensed. This data is then usedin the generation of the stimulation signal in order to be supplied witha specified relation (e.g. match or avoid) to the sensed endogenousactivity. Additionally, an envelope based upon a band-pass endogenousEEG signal can be applied with a phase which either positively ornegatively reinforces the endogenous activity 126, or which occurs witha specified relationship (i.e. phase, time, relative frequencydifference) to this activity.

Several methods may be used to positively or negatively reinforceendogenous activity or to achieve a different advantage. In the methodshown in FIG. 10, the treatment program 300 selects one or morestimulation signals 110, from the database 20 of the implantable system10 a. In the next step data are sensed 112 and the sensed data areprocessed in order to obtain a measure of a relevant characteristic 114of the sensed data. Examples of relevant characteristics are: phase of aspecific frequency; the peak frequency of a frequency band; the spectralprofile of a portion of epileptiform activity; and, the relative powerof a frequency band compared to a reference band of activity, which maybe the same band at a different time. Neurostimulation is then providedwhereby the stimulation signals are adjusted according to this measureso that these positively or negatively reinforce endogenous activity116. In other words, the relevant characteristic can be the phase of anendogenous rhythm, and the neurostimulation signal can be provided witha time delay to be either approximately in-phase or out-of-phase withthe endogenous signal. In addition to matching or avoiding matching thespectral composition of the endogenous activity, the amplitude of asensed signal can be related to the amplitude of stimulation signal.This would be useful in the case where larger tremor activity results ina neurostimulation signal of larger amplitude. Step 116 may entail usingstimulation signals which are selected and subsequently modified by thestimulation subsystem 14, according to one or more measures of therelevant characteristics in order to provide signals which areinhibitory or excitatory with respect to the endogenous activity.

Yet another alternative method is shown in FIG. 11. Rather than usingpre-defined stimulation signals, as in FIG. 10 data can be sensed 120,and this sensed data can be processed 122 to select or create thestimulation signals based upon one or more measures of the relevantcharacteristics of the data 124, prior to stimulation occurring topositively or negatively reinforce endogenous activity 126. In oneembodiment, the sensed data can be obtained 120 and then processed 122by filtering it from 4-8 Hz to determine the endogenous theta activityof the subject, and the stimulation signal is then created based uponthe relevant characteristics such as the peak frequency and phase of thefiltered signal 124. This stimulation signal is then applied toreinforce endogenous rhythms, either positively or negatively 126, andapplied relative to the phase of the endogenous rhythm. The envelope ofthe power of the filtered activity can be used to modulate a carriersignal that entrains neural activity better than the endogenous spectralconstant, in order to synchronize or desynchronize activity neuraltargets. In any case, the stimulation signal derived from sensing theendogenous signal can be stored and subsequently presented withindependent delay, at different electrodes. This method can be used tosynchronize or desynchronize neural activity related to disorders whichmanifest abnormalities of synchronization, such as tremor, epilepsy, ordepression. Another method is to create the stimulation signal itselffrom features of the sensed data, such as can occur by narrow-bandfiltering the EEG to obtain the envelope of activity related to aparticular structure, and then presenting this envelope as a signalhaving an amplitude which is adjusted in relation to the endogenoussignal. A proportional-amplitude frequency-matching control law circuitis another manner of accomplishing this type of signal. Aproportional-amplitude frequency-matching control law circuit is anothermanner of accomplishing this type of signal

In one embodiment of the method which utilizes endogenous rhythms increating the stimulation protocol, the stimulation signal is chosen tohave a frequency which is slightly above, or slightly below the spectralfrequency of the endogenous signal, for example, in order to entrain thenatural rhythm at faster or slower rate, respectively. In anotherembodiment, the stimulation signal is chosen to have a frequency whichis considerably above, or below, the spectral frequency of theendogenous signal, for example, in order to decrease the risk that thestimulation interferes with the endogenous activity. The frequencydifference between the endogenous rhythm(s) and the stimulation signalcan be determined empirically in an automatic or semi-automatic manner,where the separation is iteratively increased until the desired resultsoccur. The frequency difference can also be an absolute value such asincreasing the stimulation frequency by 2 Hz relative to the sensedoscillation, or can be a percentage such as increasing the stimulationfrequency by 10%, relative to the average frequency of the endogenousrhythm. In another embodiment, in steps 122, 124, and 126, the filteredsignal is amplified and used as the stimulation signal provideconcurrently or subsequent to the sensing operation.

Additional Spectral Considerations and Embodiments.

When selecting parameters for a stimulation signal, such as anamplitude-modulated carrier signal, the spectral characteristics of thecarrier are as important as the modulation rate. For example a carriersignal of 200 Hz which is amplitude modulated at 3 Hz, has a spectralenergy in a very different band than when a carrier of 100 Hz is used.The power spectrum of an amplitude modulated sinusoid signal will showenergy at the carrier (i.e. 200 Hz) and at 2 side-bands which areseparated from the carrier by the frequency of modulation (197 Hz and203 Hz). This signal will not have any energy at 3 Hz. However, theneurons in the brain will act as non-linear rectifiers that increasetheir firing during each rise of the envelope of the modulated signal.Accordingly, neural activity will be entrained at the modulation rate,although no energy occurs in the original signal at this rate.

When the spectral energy of the carrier is increased, for example, tovalues above 0.5, 2, or 4 kHz, a threshold will be found which is abovethe low-pass characteristics of the a cells firing capability (e.g., dueto upper limit of firing). The modulation rate of this signal may becomethe functional stimulation rate in this instance. The spectral contentof high-frequency carriers will affect the ability of the signal toentrain neurons at the modulation rate and for transmission of thesignal through tissue. The use of modulated carrier signals, where thecarriers have spectral frequencies far above 100 Hz may be morebeneficial in some applications. For example, in some individuals, 100Hz energy may lead to seizure initiation rather than inhibition, andusing energy far beyond this frequency range is preferable. Rather thanusing an amplitude-modulated carrier, a high-frequency carrier-signalcould be mathematically combined with a lower frequency stimulationsignal, and would ride on top of it (i.e. the stimulation signal can beadded to the carrier rather than multiplied with it). In thisembodiment, the modulation signal would preferably be in the range of70% to 90% of the energy and the supplementary (high-frequency) signalwould be on the order of 30% to 10%. In other words, for example, aprimary signal of sine wave from 0.1 Hz to 20 Hz with secondary signalconsisting of, for example, a noise signal or a second sinusoid issuperimposed. This superimposition can be done to increase the efficacyof the stimulation, energy transmission and reduce the risk oftolerance, where the secondary signal is about 20% the magnitude of theprimary signal.

In addition to the embodiments described, the neurostimulation signalcould comprise a modulated carrier, where the modulation rates arebetween approximately 0.1 Hz and 20 Hz, and the amplitude-modulatedcarrier signals are periodically or continuously varied in theirspectral profile. One reason for this variation would be to increasesignal transmission through tissue or decrease habituation andtolerance. A sinusoidal waveform that has higher frequencies, such asharmonics, to assist in recruiting the neural response may also be used.In a general embodiment, the method includes selecting or adjusting thefist stimulation signal which is preferably a signal is a non-pulsitilewaveform, (e.g., a sinousoid), which has been selected in order toprovide treatment, and then combining this with a second signal which issuperimposed in order to provide a secondary advantage such as a bettertransmission from electrode to the tissue or through the tissue itself,better entrainment of a tissue target, reduction of an unwantedside-effect, or differential stimulation of a particular subset ofneurons. Amplitude modulation does not have to occur with a depth ofmodulation of 100%, and the depth of AM can be a parameter of thestimulus protocol which can be set or roved.

Generally then, these principals can be embodied in the followingpreferred method. The first step of the method a first stimulationsignal is selected and adjusted to provide therapeutic benefit. In thesecond step of the method, a second stimulation signal is combined withthe first signal, and iteratively adjusted, in order to provide anadditional advantage. The additional advantage can be decreasedside-effects, increased transmission, etc. When 2 or more stimulationconduits are close enough for their fields to interact, the two signalscan be supplied by these conduits (although this will only provide foraddition of the two signals and not multiplication). If the first andsecond signals are combined by multiplication then the complex waveformwill often resemble an amplitude modulated waveform, especially when theamplitude of the first and second signals are similar. If the first andsecond signal are combined by addition, then the combined signal willoften approximate a signal which looks like the perturbation of onesignal by the other, especially when the first and second signaldifferent in magnitude by a factor of 2 or more. When the stimuli arenon-pulsatile carrier frequencies, is contemplated that the spectralcontent of first signal will normally be different from the spectralcontent of the second signal by a factor of at least 2 and theamplitudes will differ by a factor of at least 3.

This use of higher frequency addition to a relatively slow frequencycarrier is important in order to improve the ability of the signal tostimulate the intended region. In fact, small changes in spectralcharacteristics of arbitrary signals as well as pulse-trains can havesignificant effects in terms of providing therapeutic benefit ofneurostimulation. The electric fields generated by the neurostimulationleads are dependent on both the shape of the electrode and also on theelectrical conductivity of the tissue. In the central nervous systemconductivity is both inhomogeneous (dependent on location and the typeof cells in that location) and anisotropic (dependent on direction ororientation of the cells with respect to the stimulation field). Theinhomogeneity and anisotropy of the tissue around the neurostimulationelectrodes can alter the shape of the electric field and the subsequentneural response to stimulation. The result of the neurostimulation iscomplicated further by the effects that the fields will have on theindividual neurons. The second derivative of the extracellularpotentials along each process will invoke both transmembrane and axialcurrents that will be distributed throughout the neuron (as can becomputed from the cable equation). In turn, each neuron exposed to theapplied field will be affected by both inward and outward transmembranecurrents and regions of depolarization and hyperpolarization. Thesetypes of complex responses to stimulation have been examined andverified in a large number of experimental preparations demonstratingthe differences between anodic, cathodic, and bipolar stimulation withrespect to activating and blocking neural activity using extracellularstimulation (Mclntyre & Grill, 2002).

Likewise, by slightly modulating a slow wave stimulation signal using ahigher frequency perturbation, the effects, due to the variations in thegenerated fields (including their functionally relevant shapes), will bedifferent. These variations can effect energy transmission andentrainment and/or can specifically affect certain neurons in order tocompensate for the limited resources available when working withimplanted systems which rely upon fields that are generated fromneurostimulation electrodes of fixed locations.

One embodiment which can be used with either electrical or magneticstimulation utilizes a modulated carrier with a center frequency ofbetween approximately 200 and 1000 Hz. And another embodiment, uses acarrier with a center frequency of between approximately 1 and 100 kHz.A band-pass noise stimulus can be used having energy betweenapproximately 0.5 and 20 Hz. The term“energy between approximately 0.5and 20 Hz” may be understood, in some embodiments, as a band of energywhich may span 1 Hz or more. For example, the band of energy may spanapproximately 4 Hz and be centered at 6 Hz, with slightly more energy atthe 2 higher frequencies of the band.

While prior art, such as the '770 application, describes using lowfrequency stimulation, the signals described here are not anticipatedfrom the prior art. The '770 a dual-stimulation strategy incorporating anon-responsive“low frequency stimulation having a primary frequency ofaround 0.5 to 15.0 hertz” in the treatment of disorders such asepilepsy, unlike the current invention, it does not describe usingamplitude modulated carrier signals having rectified energy primarilybetween approximately 0.1 Hz and 20 Hz and also does not describe usingamplitude-modulated carriers where the modulation frequencies arebetween 0.1 Hz and 20 Hz, and in which the spectral content of thecarrier signal is varied in order to improve therapy (e.g., increasesignal transmission through tissue, increase entrainment of neuraltissue, or decrease habituation and/or tolerance). The methods describedhere include embodiments where sensed data is used to create thestimulation signal and, based upon the band-pass of the amplifier, theresulting stimulation signal contains spectral content between 0.1 Hzand 20 Hz. The inventive methods also may be realized using control lawsand control circuits where the parameters which guide the controlprocesses, or the processing of the signals sent to or from the controlprocesses, are set or adjusted in order to produce methods or signals adescribed herein. It is understood that stimulation strategies whichutilize sensed data, with or without control laws, may be adjusted anddesigned to incidentally, periodically, and even responsively, providestimulation with the signals and strategies described herein, and suchimplementation is understood to be part of the claimed currentinvention.

The invention provides methods and systems for improving treatment byproviding a stimulation signal which sweeps or alternates a stimulationparameter such as the repetition rate, the instantaneous spectralcontent of the stimulation signal, or the center-frequency of aband-pass signal, using values for the parameter which have been shownto provide desired therapy during a selection procedure. Carrier signalswhich are modulated to provide a rectified signal with spectral energybetween approximately 0.1 Hz and approximately 20 Hz, are a preferredembodiment, although for applications related to, for example, corticalstimulation, modulation may occur using stimulation signals withalternative spectral signatures, for example, those of the gamma range(i.e., 40-100 Hz). The carriers can be selected based on their abilityto entrain target tissue. A band-pass filter can be used to filterendogenous EEG activity, sensed from a sensor, in order to generate oneor more low frequency stimulation signals which are in-phase with, andwhich drive, the endogenous signals of different brain structures (e.g.,the thalamus, basal ganglia, amygdale, or hippocampus) or which has someother phase relationship to the naturally occurring signal.

In another embodiment, the stimulation signal is comprised of amodulated noise carrier. If the noise is low passed, the resultingstimulation signal will approximate a sinusoid with random fluctuations.Accordingly, the signal may never repeat since no two segments of thesignal will be the same, unless of course the signal is stored in acircular buffer, in which case the repetition rate will be the inverseof length of the buffer. The different shapes which are produced by therandom fluctuations of this signal may be advantageous, over using anunchanging stimulation signal, since these have a greater probability ofstimulating various types of neurons within the target tissue, and maybe less prone to certain types of habituation or adaptation. Further,the transfer of energy through the neural tissue may be somewhatdependent upon the shape of the stimulation signal, and may also affectthe ability of a stimulation signal to stimulate different neurons.

Further, rather than using a stimulation signal that oscillates, one canuse a slowly alternating DC stimulation (this may approximate a squarewave signal), where the signal stays at some positive voltage value fora given amount of time and then switches to a negative value after a 1or 2 second period (or when a seizure is predicted to occur in the nearfuture). As in the case of the 3 Hz stimulation, a simple occasionalswitch in polarity may cause the extra-cellular environment to bedestabilized to the point that seizures cannot be generated, but theinhibitory effect of slow wave stimulation on learning and othercognitive processes can be avoided.

A method of treating a disorder comprising alternating the treatmentprotocols between 2 or more candidate treatment protocols (or parametervalues), wherein a first candidate protocol provides a first therapeuticbenefit and a second candidate protocol provides a second therapeuticbenefit, and said first and second therapeutic benefits are at leastpartially independent and may be related to treating two types of eventsrelated to the disorder. The two protocols can be provided in anoverlapping, interleaved, alternating, or roving fashion. The protocolscan provide stimulation according to signals which are supplied to thesame stimulation conduit, different conduits, or different conduitswhich are close enough that their fields interact.

The method of treating a disorder in which the stimulation occurs with astimulation signal comprised of at least two components, wherein eachcomponent is directed towards a different symptom of the disorder.

The method of treating a disorder comprises providing a stimulationsignal with at least two components, wherein the first component istherapeutic but also causes an unwanted side effect and the secondcomponent is provided, selected, or adjusted to decrease the unwantedside-effect. The side-effect could be stimulating a neural targetindiscriminately, and the second component causes an increase in theselectivity of the stimulation or the side effect could be theinadvertent disruption, enhancement, or entrainment of a particularendogenous rhythm and the second component can be a reduction in thisinadvertent effect.

The method of treating a disorder comprises providing a stimulationsignal with at least two components, wherein the first component istherapeutic and where the second component is provided, selected, oradjusted to make an improvement of the first component. The improvementcould be stimulating a neural target more specifically, decreasing thedisruption, enhancement, or entrainment of a particular endogenousrhythm which is not related to the treatment benefit, enabling bettertransmission of the first component with less power, decreasingimpedance at the electrode-tissue junction.

Changing the Fc while maintaining a constant modulation rate mayincrease energy transmission or entrainment of a neural target. Oneembodiment of the invention describes methods to permit increasedstimulation efficacy, by tailoring the Fc and Mf characteristics toincrease transmission of the stimulation signal. Changing thesecharacteristics can also improve therapy by decreasing the chance ofhabituation or adaptation by the tissue. The carrier frequency (Fc), orthe modulating contour or its frequency (Fm) can be adjusted atspecified or random intervals, or according to sensed data. Sensed datamay be used to provide the modulation envelope for a carrier signal, orthe timing of a pulse signal, in applications where sensed data is fedback to the brain in a closed loop fashion to promote or deter thatactivity. This method is an advantage when the modulated carrier, orwindowed pulse train or pulse signal, is more efficacious in entrainingtissue than stimulation which simply provides the modulation envelopeitself.

The two signals can be generated by two different control laws, orcontrol circuits, and provided as the stimulation signal at one lead.These methods can be accomplished wherein, the two or more components ofthe stimulation signal can be generated by two or more different controllaws, or control circuits, and provided as the stimulation signal at onelead.

The present invention can assist in entraining endogenous signals vianeurostimulation. In one alternative embodiment shown in FIG. 11,neurostimulation occurs using a stimulation signal that is based uponthe output of a band-pass filter that filters endogenous EEG activitythat is sensed from a sensor. The band-pass may be set to pass only lowfrequency (e.g., 4 to 8 Hz) EEG which can be used to generate a lowfrequency stimulation signal which is in-phase with the endogenouslygenerated signals (for example, the signals generated structures such asthe thalamus, basal ganglia, amygdale, or hippocampus). One rational forthis approach is that it may decrease the risk that the stimulationinterferes or attenuates the naturally occurring rhythms of the brain.In this manner the neurostimulation acts to drive or enhance endogenoussignals rather than occurring arbitrarily. In this example, thestimulation signal does not have a specific and definable frequency ofstimulation since the waveform would rove in its frequency (and possiblyamplitude) characteristics based upon fluctuations in brain activity.However, it would often be primarily comprised of approximately 4-8 Hzactivity, if the sensed signal was coming from a sensor which sensedactivity of a brain generator which produced oscillations in thisfrequency range, such as the hippocampus.

Methods for Selecting and Evaluating Treatment Protocols.

A number of methods are needed to increase the chance for providing andmaintaining successful therapy during treatment. Even if the parametersof a default stimulation protocol are initially well chosen, over time,the stimulation signal may loose its therapeutic efficacy. In this case,therapy should be altered in an attempt to reestablish benefit. Severalmethods can be used in order to evaluate how well alternativestimulation parameters (including those of the partial signals) mayserve to provide therapy compared to the baseline condition (i.e. thecurrent default protocol). The methods generally adjust at least oneparameter of the treatment protocol, and may be invoked if sensed dataindicates that treatment benefit has decreased below a specifiedcriterion. These methods can also be invoked periodically, for example,to simply explore if other parameters can provide advantages in theprovision of therapy. Methods are described which automatically, orsemi-automatically, under user guidance may be used to selectappropriate values for the parameters of the treatment program, mostroutinely to create the signals used in the stimulation protocol.

In one embodiment, shown in FIG. 12, a method is illustrated wherein thevalue of a treatment parameter is varied one or more times and senseddata are collected and processed in order to determine if one or morealternative values can successfully provide improved treatment. Thismethod can be applied to many disorders, but is illustrated in thetreatment of epilepsy. In FIG. 12, the method is used for evaluatingepilepsy treatment protocol parameters and accordingly the test scorewhich is evaluated is a seizure score. However, it is obvious that indifferent disorders this test score can be related to symptoms of thoseparticular disorders, and can be, for instance, test scores related totremor size, duration, and location, or to neurotransmitter levels, andcan be multivariate test scores related to data sensed by multiplesensors.

Parameters can be compared by creating a histogram of the number ofseizures which occurred during each of the values tested for thestimulation parameter, with the bin-width being equal to the step sizeof the tested parameter or bin-width being amalgamated over a specifiedrange. One or more stimulation parameters can then be selected and usedduring treatment based upon the seizure test score for the parameters,where parameters which meet a criterion value (produced the lowestscores) are chosen. In one embodiment of the present invention, thestimulation frequency is iteratively swept from approximately 0.5 Hz toapproximately 20 Hz, in 1 Hz steps or at rate of 1 Hz per N minutes, andthe seizure test scores during each frequency of stimulation arecalculated. Alternatively, after a treatment with each frequency ofstimulation a probe stimulus is applied at or near the stimulated regionand an evoked response (e.g. epileptiform activity) is collected. Thefrequencies of stimulation which produced a desired characteristic inthe response (e.g., the smallest amplitude or shortest duration evokedresponse either of which may be representative of decreased reactivity)can be selected to be used during the subsequent treatment.

In step 130 neurostimulation is provided according to a protocol, whichmay be a preferred protocol which has previously been selected, andwhich provides a particular stimulation signal to at least oneSEST-probe 31. In step 132 baseline data are obtained and are thenprocessed in order to obtain a baseline seizure score 134.

The processing of the data 134 can lead to one or more baseline scores.A score can be a single multivariate score which can be based upon thenumber, size, and type of seizures which occurred. For example, thescore can be computed from a weighted multivariate equation whichcombines number, size and type using an equation 4N_(L)+2N_(S)+4(T)where NL is the number of large seizures (which may be defined as havinga magnitude or duration which surpasses a specified criterion), N_(L) isthe number of smaller seizures (that are below the specified criterion),and T is the type of seizure.“T” may be assigned a number based upon theposition where the seizure activity originated (e.g., which electrodesdetected its emergence first) and the number related to its relevance tothe disorder, or the number can be based upon other characteristicswhich are deemed to be related to seizure type or severity.Additionally, more than one score can be computed wherein each score isrelated to a different symptom of the disorder. This latter type of testscore can be termed a“symptom score”. When done over two or more testingperiods, each test score can include statistics related to the scoresuch as mean and standard deviation.

In step 136 one or more parameter values of the protocol are changed.Parameter values can be, for example, the duration or magnitude ofstimulation, or the time between stimulation periods, and stimulationagain occurs 137 with parameter value(s) set to the new value(s). Testdata are then sensed 138 to permit the evaluation of the effects of thischange. In step 140 the test data are evaluated to provide one or moretest scores and in step 142 the at least one baseline seizure score andat least one test seizure score are compared to obtain a test result.The comparison operation may utilize one or more statistical criteria inorder to ensure the test result occurred for at least a specifiedprobability level. The test result may be binary, being“positive”or“negative”, or may be quantified. If the test result is negative thenthere is no difference between the baseline and test seizure score. Ifpositive, then a change has occurred and the test result may also have asign value associated with it representing the direction of the change.The difference between the two scores may have to reach a criterion,which may be a statistical criterion or simply a threshold which isrelated to the size of the difference in order for a positive result tooccur.

In step 144, the test results are evaluated and a treatment parameter isaltered, or not altered, as may occur according to an algorithmimplemented by a therapy program 300. As stated, the test result whichis passed from step 142 on to step 144, may be binary, may have astatistical significance value attached to it, and can also have aquantitative aspect, such as the size and direction of the differencebetween the two scores or the scores themselves.

In one embodiment, in step 144, the treatment program dictates that ifno improvement was found, comparison to the of the test seizure score tothe baseline score produces a negative result, the value of theparameter value is changed (e.g., increased), and step 137 is repeated(arrow). A positive result causes step 146 to occur (although this maybe made contingent upon the direction of the change). In an alternativeembodiment, the test result is ignored, and the value is changed beforerepeating step 137, this can occur in order to provide two or more testresults prior to causing step 146 to occur.

In step 146, the program is terminated and one or two other actions mayalso occur. In one embodiment, a value which produced an improvement ofthe test score relative to the baseline score is used to set theparameter value of the protocol that was being tested, and this is thenused to provide subsequent therapy. In an alternative embodiment, whenseveral test scores were obtained, an algorithm evaluates the scores andselects one or more values that resulted in positive test scores. Forexample, the test scores can be ranked and the values associated withthe top (or bottom) 3 scores can be selected for use in the treatmentprogram. Additionally, the scores may be symptom-scores which arerelated to two or more distinct types of events, and the meta-analysisprogram selects the values which produced the highest scores for two ormore symptoms scores. These values can then be used by roving methods todeter the two different symptoms when roving or alternating stimulationsignals are implemented.

In one very useful alternative embodiment, the parameter which ischanged is the time between stimulation periods, and in step 144 theinter-stimulation period is iteratively increased until an a positivetest result is obtained. In step 146, the meta-analysis algorithm maythen cause the inter-stimulation period to be decreased by a specifiedamount such as decreasing the interval to the last inter-stimulationperiod which did not produce this change in test seizure score comparedto the baseline seizure score. When“inter-stimulation period” is theparameter that is investigated using this method, then this will lead toless than continuous stimulation while still providing similardeterrence of seizures, and will utilize less energy, and potentiallycause less side-effects and be less prone to habituation. This methodcan be used so that advantageous inter-stimulation intervals can bedetermined to treat various disorders. Generally, stimulation occurs byperiodically applying non-responsive or basal stimulation, andincreasing the duration between consecutive periods of stimulation untilthe number of the unwanted events increases (as may be determined byanalysis of sensed data indicating a score which doesn't meet acriterion), and then decreasing the inter-stimulus duration below thisamount. By using this technique power is saved while efficacy oftreatment is maintained above a specified level.

A subset of the steps of this method can be adopted in order to provideadditional routines useful in evaluation of stimulation treatment. Step130 can be omitted in order to compare the values used in the teststimulation to a non-stimulation baseline state. Additionally, adifferent set of parameter values can be relied upon in order to simplyevaluate different values of the treatment protocol from time to time.For example, by performing steps 137, 138, and 140, two or more times(i.e. stimulate, sense, process to obtain test scores) and thenperforming the meta-analyses of step 146 one or more preferred valuescan be selected to be used in the treatment protocol. By only includingsteps 137 to 146, and using a reference value other than the baselinescore, the test scores can be compared to a user defined criterion(i.e., the reference value). In the case when the test result iseither“positive” or“negative”, these terms will obviously be relative tothe criterion being used. A score of 3 would fail if the criterionwas >5 and pass if it was <5, but in a preferred embodiment, theterms“positive” signifies that a test score has successfully met athreshold set by the treatment criterion.

Conversely, rather than being omitted, steps can be repeated. Further,if steps 130, 132 and 134 occur multiple times, several scores can beobtained and statistics can be computed on these to determine if anydifferences are“real” with respect to the variance of the test scoresobtained with different parameter values. Statistical estimates can beuseful in order to enable subsequent statistical comparison of thebaseline scores to test scores, in order to avoid changing the protocolaccording to results that occurred by chance or were unreliable.Obviously steps 136, 138 and 140 can be repeatedly done as well toprovide statistical estimates for the test-result data. Additionally,although step 132 occurs after step 130 in the diagram, the baselinedata can be sensed approximately at the same time that theneurostimulation occurs, for example, in periods after one or moreintervals of neurostimulation, and sensing can occur in an interleavedfashion with the provision of neurostimulation according to theprotocol.

The method shown in FIG. 12 can be accomplished periodically to ensurethat stimulation parameters are effective and advantageous for example,once a week or once a month. If there are diurnal related changes in adisorder, this method can be accomplished more than once a day and, forexample, evening and morning protocols can be established separately.The method may be applied to any aspect of the treatment protocol, andnot only to the stimulation protocol. Notably, when sensed data are usedto create the stimulation signal, as may occur using control laws, themethod can be applied to adjust the values related these laws. Ratherthan sensed data being evaluated automatically, it is likely that thetest results will often be provided to the patient programmer 500 sothat these can be evaluated by a user, who will then select successfulcandidate values. In addition to sensed data obtained from implantedsensors, test scores can be related to behavioral, cognitive, oremotional measures indicated by the patient using the programmer 500. Inaddition to parameter values related to the stimulation signal,different roving parameters relating to the rate of roving can beassessed using this method.

An alternative method evaluates two or more values of a parameter duringthe testing period, rather than testing these in discrete iterations asgenerally occurs in the method of FIG. 12. Over a specified time perioda parameter such as the frequency content of the neurostimulation signalcan be iteratively roved or alternated with potential parameter valuesand the effects can be assessed so that advantageous parameters areselected for use in treatment. FIG. 13 demonstrates an embodiment ofsuch a method wherein a step 150 comprises applying neurostimulationaccording to Protocol 1, which uses a strategy such as roving oralternating to test values related to specific parameter. For example,the frequency is roved across a specified frequency range (e.g., eithercarrier frequencies or modulation frequencies are iteratively varied).In step 152, the test data are subsequently sensed after each newiteration, or after the data from several iterations have been averaged,and then the test data are processed to determine the seizure scoresassociated with each value of the tested parameter 154. One or morestimulation parameter values can then be selected by the meta-analysisalgorithm and used during treatment based upon the seizure score for theparameters. In one obvious embodiment, the parameters which produced thelowest scores are chosen 156 and used to create protocol 2 158. In oneembodiment of the present invention, the stimulation frequency isiteratively swept and the number of seizures which occur during eachfrequency of stimulation are recorded, and at least 2 or more parametervalues which resulted in the least number of seizures during the testingperiod are then selected to be used in during the subsequent treatmentwith Protocol 2 160. In another embodiment, only 1 parameter is chosenbased upon a comparison of seizure scores.

The method may only include steps 150 trough 160, in order to selectvalues for the stimulation parameters and provide treatment, or may alsoinclude steps 162-164 to provide a secondary component of the methodwhich allows for adjustment of Protocol 2. In step 162, treatment dataare sensed and evaluated to determine if treatment meets a specifiedtreatment criterion selected by the treatment protocol. This comparisonproduces a test result that, again, can be binary, quantitative (withsign indicating direction of change), and/or statistical. In step 164three different results may occur which are illustrated by threedifferent paths. Path 162 a is followed when a treatment criterion ismet, which simply returns the method to step 160, so that stimulationagain occurs using the current protocol. When treatment criterion failsto be met, step 164 can follow paths 164 b or 164 c. Path 164 b causesthe method to be restarted from scratch and new values are obtained forthe parameter. Path 164 c causes step 166, in which adjustment occurs asis defined in the treatment program 300 (e.g. use a past successfulparameter value). Step 166 can also be utilized when treatment criteriaare almost met and a relatively minor adjustment (e.g., increasingvoltage slightly) may again cause the criteria to be met. The situationsin which 164 a, 164 b, and 164 c occur can be dictated by a treatmentevaluation algorithm used in the treatment protocol during step 164. Inthis manner, the type or magnitude of treatment failure can be evaluatedand can result in either changing the stimulation protocol slightly inorder to attempt to produce treatment success or can require stimulationparameters to be re-evaluated in a more comprehensive manner. Onecriterion for returning to step 150, can be defined as continuednegative test results having occurred a specified number of times usingstep 166 within a specified time period. FIG. 13. also demonstrates amethod of adjusting a the protocol, a little or a lot, based uponcomparison of treatment response to treatment criterion, and whether thecomparison failed by a little, or a lot. In other words, the size of thetest result can determine subsequent operations of the method.

Transcranial Magnetic Stimulation Applications.

US 20030028072 entitled ‘Low frequency magnetic neurostimulator for thetreatment of neurological disorders’ (the '072 application) describes asystem for treating neurological conditions by using low frequencytime-varying magnetic stimulation. The application describes applyingenergy in a range below approximately 10 Hz to the patient's braintissue and also describes an implantable embodiment where directelectrical stimulation is used. The '072 application describes using acarrier waveform of about 100 Hz which is pulsed at different rates.Unlike the '072 application the current application describes matching,adjusting, or avoiding matching the rate or pattern of stimulation to,or in relation to, endogenous rhythms in the brain (especially thosebelow about 18 Hz) in order to increase the efficacy of treatment. Byadjusting the modulation or pulsing of the stimulation fields so thatthese match or resonant with the internal rhythms of the brain, the slowfrequency rhythms (or slow frequency amplitude modulation of highfrequency pulse stimuli) can be augmented (Bawin et al, 1973) orinhibited. Magnetic stimulation using two or with more coils whosesignals produce a vector field having spectral characteristics which aredifferent than the constituent signals can be implemented by the systemsof the '072 application.

FIG. 15 Shows a device 10 bfor providing repetitive and/or responsivetranscranial magnetic stimulation to a patient 38, who may be sufferinga neurological disorder, such as been described in the '072 application.The device is a hand held or head-mounted structure containing circuitryto provide TMS from at least 2 magnetic-coil SEST-probes 31 e and 31 e′.The methods and systems of device 10 a can be implemented in TMS device10 b, which can also communicate with a patient programmer 500. An ACpower source for device 10 bcan be provided. The methods for usingpartial signals, roving protocol parameter values, and adjustment (e.g.matching) to endogenous activity are all applicable to stimulationprovided by device 10 b. The methods which involve matching the rate ofstimulation to endogenous rhythms in the brain in order to increase theefficacy of treatment can be used in the rTMS treatment, where thepulses of the treatment are matched to internal oscillations. This typeof treatment could be enabled, for example, using an EEG amplifier andan electrode attached to the surface of the patients head. The amplifiermay be physically disconnected from the electrode during periods ofpulsed magnetic stimulation so that currents are not induced in theelectrode wire. The EEG measurements can be obtained in the periodsbetween treatment pulses, which may occur in a regular, periodic manneror in response to evaluation of the EEG that is sensed. The use ofpartial signals can also be achieved by configuring the geometry of twoor more stimulation coils appropriately with respect to the intendedneural target.

When the rTMS treatment is used for treating disorders such asdepression, the stimulation is can be primarily directed to the frontalareas of a patient's brain, and within the frontal areas the treatmentmay be primarily lateralized to either the left or right hemisphere,although both hemispheres can be treated. TMS applications can includeinduction or facilitation of anesthesia either with or withoutconcurrent drug therapy, electrochemotherapy, therapies that affect thepermeability of the blood brain barrier, applications of TMS to strokerecovery and other types of adaptation, the modulation of cellular andmetabolic signals, and other therapeutic methods and applications.

Alternative Embodiments

It is recognized that the systems and methods of the present inventioncan be implemented using alternative neurostimulation devices andsystems, without departing from the inventive principles disclosedherein. For example, rather than utilizing a sensing, stimulation, andcontrol subsystem which provides therapy as guided by a treatmentprotocol, alternative devices may utilize functionally equivalentembodiments which rely upon treatment“rules”, “templates”, or“modules”.

For example, U.S. Pat. No. 6,480,743 ('743 application) describes adevice and methods which will be termed the NPACE system. The componentsof the device are : 1. detection subsystem and waveform analyzer; 2.stimulation subsystem and stimulation waveform generator; and, 3. acontrol interface. These are functionally equivalent to the 1. sensingsubsystem and evaluation protocol; 2. stimulation subsystem andstimulation protocol; and 3 control subsystem and treatment program,respectively, which are utilized by the current invention. The NPACEsystem uses a method of detecting events which is similar to the eventdetection and evaluation of symptoms utilized in the current invention,and therapy templates of the NPACE system are similar to stimulationprotocols utilized herein. It should be recognized that the systems andmethods of the current invention can be implemented in the NPACE devicein a similar fashion as described here, with different nomenclature,without departing from the spirit of the invention, and the steps of itsmethods, and strategies.

US20050240242 ('242 application) describes a device and method whichwill be termed the NBION system. The components of the device are: 1.sensor array and signal conditioning circuit; 2. control circuit; 3.output state circuit and stimulating electrode array, which arefunctionally equivalent to the 1. sensing subsystem; 2. controlsubsystem; and, 3. stimulation subsystem, of the current invention. TheNBION system utilizes control laws and observers to provide neuralmodulation in the treatment of disease wherein a neural state iscontrolled to be maintained within a specified range. The neural stateis similar to some of the types of sensed data of the current invention.The methods, algorithms, strategies, and principles of the currentinvention can therefore be easily implemented in the NBION system, andcan provide methods for setting, evaluating, and adjusting theneurostimulation signals and treatment parameters of that system.

When using input signals, via control laws, event detection, or otherstrategy, to produce a stimulation signal which is used forneurostimulation, the output may not specifically defined has havingconstant properties since it is configured according to thecharacteristics of the sensed data. Nonetheless, control laws strategiescan produce signals, partial signals, and vector fields similar oridentical to those described herein, merely incidentally. It isunderstood that the advantageous characteristics of the signals andmethods described herein can be incidentally produced without departingfrom the spirit of the inventions, and such incidental or non-determinedcreation of equivalent stimulation (for example, a signal with most ofits energy below 20 Hz which is non-deterministically created by theoutput of a band-pass filter, a carrier signal which is approximatelymodulated according to the envelope of selected sensed activity, or twosignals each directed to treat a different symptom of a disorder) isconsidered to be a subset of the disclosed methods. The disclosedmethods cause roving to occur in a formalized and controlled manner sothat the roving parameters provide increased therapeutic benefit to thepatient.

Treatment.

Targets for therapy can be any part of an organism. Targets may beneural, vascular, in the brain spinal chord, heart, digestive system, ormuscle or organ. Targets used in the treatment of epilepsy, migraine,psychiatric, neurodegenerative, memory, eating, pain, sleep, mood,anxiety, movement disorders, and tremors may include, but not be limitedto the one or more regions of the hippocampus, brainstem, thalamus,cortex, and spinal chord, or at least one nerve structure comprises atleast one of a trigeminal nerve, a branch of the trigeminal nerve, atrigeminal ganglion, an ophthalmic nerve, a branch of the ophthalmicnerve, a maxillary nerve, a branch of the maxillary nerve, a mandibularnerve, a branch of the mandibular nerve, a greater occipital nerve, abranch of the greater occipital nerve, a lesser occipital nerve, abranch of the lesser occipital nerve, a third occipital nerve, a branchof the third occipital nerve, a facial nerve, a branch of the facialnerve, a glossopharyngeal nerve, and a branch of the glossopharyngealnerve.

The stimulation methods described herein can be used to stimulate tissuein order to modulate electrical, chemical or other types of activity, aswell as cellular and developmental processes. The methods and systemsfor generating electrical fields can be applied to therapies andprocedures related to growth and differentiation of cells (e.g.,pre/post-implantation procedures related to stem or fetal cells),including neural differentiation which is induced by electricallystimulated gene expression (Mie et al, 2003). Further, the methods andsystems can be used in conjunction with treatments such as chemotherapyin order to potentiate the response to or uptake of a chemotherapeuticagents or can be used independently as an anti-cancer therapy whereelectrical treatment of malignant tumors and neoplasms is provided byapplying a stimulation approximately to affected tissue. Additionallythe methods and systems can be used to modulate gene transfection, oralter the uptake of drugs by cells (e.g, electroporation,electropermeabilization, DNA electrotransfer) and can also be applied tomodulate cellular growth and proliferation (Miklavcic et al., 1998;Faurie et al, 2004; Pucihar et al, 2002; Ciria et al, 2004; Cucullo etal., 2005). In these cases, great advantage may be obtained from usingpartial signals when stimulating focally in the 0.1 Hz to 20 Hz range,with respect to decreasing unwanted side-effects and assisting inpatient tolerance to treatment. The stimulation can be used to altercellular functioning, particularly protein synthesis, and alter synaptictransmission by modulating the production of neurotransmitters (Cuculloet al, 2005; Benabid & Wallace, 2005). The techniques can be used forwound healing, bone repair, and modulation of cellular activity and canalso be used for prophylactic treatment. Further, the methods andsystems can be used in dermatological treatment and cosmeticapplications such as tissue reshaping and skin tightening, for example,by causing controlled patterns of damage, electroporation, thermalinduction, wound healing, and collagen growth in selected tissue areas,such as skin, muscle, and fat. The systems and method can also be usedto stimulate drugs or drug release, for example drugs stored withinnano-particles which release these drugs when triggered by specifictypes of energy. The creation and utilization of partial signalsdescribed herein can be provided by implanted electrodes, or by opticaltransducers, or by external stimulation devices such as rTMS deviceswhen used for applications such as electrochemotherapy, electroporation,and other relatively acute interventions. Stimulation, especially TMS,can be used to promote and modulate sedation and anesthesia.

The systems and methods described herein may be used in the treatment ofpsychiatric conditions, migraines, pain, tremor, OCD, anxiety, mania,and depression, traumatic brain injury or cerebovascular accidents,strokes, thrombosis or aneurysm, and can also be applied to stimulationof other areas of the body such as the cardiovascular system, digestivesystem, skin, muscle, spine, nerves related to pain, or other tissues ororgans. Further the invention can be directed towards the provision ofdiagnostic applications such as neurological, neurosurgical, andneurophysiological testing, especially with respect to studies involvingfreezing (e.g., creating a functional lesion), activating, or functionalmapping of selected regions, and testing of nerve conduction and nervevelocity in the diagnosis of any nerve degenerative disease. Testing andpromotion of recovery can also be accomplished in post-TBI, and otherdisorders for which compensatory adaptation and retraining may promotedusing stimulation. Stimulation of tissue can also be accompanied by, andtime-locked to, sensory stimulation, can occur during tasks, and canoccur during a period following drug administration.

The stimulation methods and systems of the current invention can be usedin conjunction with priming techniques. For example, subthreshold orsuper-threshold stimulation can occur prior to, stimulation with any ofthe described techniques in order to facilitate, enhance, or diminishthe response to the subsequent stimulation (e.g. Lyer et al, 2003).Likewise, post-stimulation modulation signals can be paired withstimulation signals in order to modulate, enhance, or diminish theresponse to the prior stimulation.

Terminology.

The following material provides a general understanding of terms used inthis specification, although these terms may have been further adjustedor modified or altered within the specification itself, or by reasonableand logical extrapolation, to achieve different specific embodiments ofthe invention.

As used herein the terms“stimulation system” or“stimulator” refers to adevice having either distributed components or which are primarilycontained within a device housing. Tissue modulation can include single(e.g. electrical), or multiple (e.g. optical and drug) therapy. Thestimulator can be a generic implantable stimulator (e.g., Guidant,NeuroPace, Medtronic) adapted to achieve the inventive features. Thestimulator can be a transcranial magnetic stimulator, or anothermodulation device, having components located partially or completelyoutside of the patient.

As used herein the term“module” refers to subroutines and hardware forrealizing device operations. Modules may use resources of other modules(e.g. memory) to accomplish features of the invention.“Subsystems”refers to one or more modules which provide operations needed duringtherapy dictated by the treatment program.

As used herein the term“stimulation conduit” can include one or moreelectrical leads, each having at least one electrical contact.Stimulator conduits can also be any conduit which relays SEST-signalsbetween SEST-probes and the device. When stimulation is drug-basedthen“fluid signals” can be transmitted by more catheters.

As used herein, the term“sensor” can refer to a device for measuring anelectrical, chemical, optical, or other physical property of thepatient. Sensors can be those described in US 20060149337, to John,entitled“Systems and methods for tissue stimulation in medicaltreatment”.

As used herein, the term“treatment program” refers a set of subroutinesto provide treatment using one or more“therapy/treatment protocols” anddetermines the parameters for the control, stimulation, sensing, andevaluation protocols, and determines, if, how, why, and when theprotocols are altered. The terms“treatment” or“therapeutic benefit” cansimply mean decreasing or deterring one or more unwanted symptoms of adisorder, or providing stimulation which is creates a therapeuticeffect. Treatment can be related to treating a disorder, or can berelated to inducing a medically/biologically related change in thepatient, such as modulating anesthesia or sedation. The treatment can bedirected towards preventing, deterring, normalizing and/or minimizingtypes of activity. The treatment program can provide therapy whichminimizes energy or amount of stimulation needed to obtain therapeuticbenefit increasing transmission of energy from stimulation sources to,and through, tissue. Treatment parameter values and protocols whichproduce advantageous effects are termed“successful”.

As used herein“stimulation subsystem” provides stimulation according tothe parameters of a stimulation protocol which determine where, if,when, and how to stimulate. A stimulus parameter value can define aspectral parameter, which relates to, for example, the amplitude, phase,and frequency of at least one component of the stimulation signal. Astimulus parameter can also be a pulse parameter, such as pulsefrequency, amplitude, width or shape.

As used herein the terms“stimulation” refers to modulation of tissuewhich can be excitation, inhibition, or other type of desired modulationof target tissue. In the case of chemical-based therapy, stimulationsignals may be include“fluid signals,” in the case of optical therapythese can include“light signals,” and in the case of electrical therapythese can include“electrical signals.”

As used herein, the terms“event”, “detection of event” or“medical event”refer to the sensing and analysis of data which confirms that abnormalor unwanted activity, such as a seizure or other activity related to asymptom of a disorder was detected, predicted, or anticipated. Eventsmay be abnormal states which have been detected or predicted.

As used herein,“symptom” generally refers to behavioral orelectrophysiological signatures or specific components of a disorder.Symptoms can include: subjective experiences; abnormal activity,response to stimulation, or can be a neurochemical level, type ofsynchronization or coherence, metabolic or cellular activity, structuralchange, or network activity; abnormal data sensed from one or moresensors; a specific pattern or level of activity; or any other measurethat is related to an abnormal trait or state related to the disorder.

As used herein,“roving” may refer to a function by which a parametervalue is formally alternated over time. A parameter value can refer tovoltage or current of a stimulation signal, and the value may be scaledor adjusted relative to impedance characteristics and/or electrodegeometry, especially with regard to the generation of partial signals.

As used herein,“seizure” generally refers to behavioral orelectrophysiological signature of an impending or existent seizure, andincludes epileptiform activity.

As used herein,“amplitude” may refer to either voltage or current of astimulation signal, and may be scaled or adjusted relative to impedancecharacteristics and/or electrode geometry.

As used herein the term“sensing subsystem” refers to a subsystem whichprovides sensing according to the parameters of a sensing protocol whichdetermines where, when, if, and how to sense with one or more sensors.The sensing subsystem can provide communication with, and power andcontrol signals to, sensors used in treatment.

As used herein the term“control subsystem” refers to a subsystem whichprovides control of the treatment and can implement a treatment program.The treatment program can select treatment protocols and parametervalues from a database memory, and these parameters may be fixed,adjusted. The control system can communicate with an external patientprogrammer, or equivalent device through communication circuitry. Thecontrol system can implement sensing, stimulation, evaluation,calibration, and testing methods and algorithms as described herein. Thecontrol subsystem can also implement control laws to enact therapy.

As used herein the term“treatment criterion” refers to a criterion towhich sensed data or test results are compared using the evaluationprotocol. The results of this comparison can determine what type ofstimulation takes place. For example, failure to meet a treatmentcriterion may cause stimulation to occur or may cause a change, or maycause a different stimulation protocol to be selected. Alternatively,success in meeting a treatment criterion may cause stimulation to behalted or may cause the same stimulation protocol to be selected again.It is obvious that the logic of treatment criterion can be inverted, andseveral criteria can be combined sequentially or in parallel in order toprovide therapy without departing from the spirit of the inventionillustrated and described in the embodiments of this description of theinvention.

As used herein,“basal signal” or“basal stimulation” refers to theapplication of stimulation intended either to decrease the probabilityof an adverse event occurring, such as a seizure, or to modulateactivity related to a disorder such as psychiatric illness or tremor.The basal signal is generally applied non-responsively, continuously, orperiodically, although it can be adjusted or selected based upon thetreatment program, time information, or sensed data.

As used herein,“base signal” normally refers to a signal which will bemodified or used to determine two or more partial signals. The partialsignals will combine to form a “vector sum field” in the tissue of thesubject which approximates the base signal.

As used herein,“responsive” stimulation refers to the application ofstimulation which occurs or is altered in response to evaluation ofsensed data, such as the detection of a medical event.

The contents of all prior art examples cited in this specification andall scientific /technical references, are hereby incorporated byreference as if recited in full herein. In the claims of thisapplication, when methods have steps which have been assigned letters,the steps may occur sequentially in the order indicated by the letters,or certain steps may occur approximately simultaneously, or in aninterleaved fashion, with other steps. The stops of the methods canoccur automatically using specialized algorithms, semi-automatically(with some manual adjustments), or primarily under the guidance of aphysician. The headers for various sections such as“Background”or“Treatmene” are intended to be descriptive only, and do not limit thescope of the material which is provided in these sections, in any way.

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What is claimed is:
 1. A device for treating a disorder of the centralnervous system comprising: a conduit set containing at least onestimulation conduit including at least one probe; a stimulationsubsystem for providing stimulation to the probe according to one of atleast two candidate treatment protocols, with each protocol having atleast one treatment parameter value; a control subsystem for controllingthe stimulation subsystem, said control subsystem operating under atreatment program designed to provide alternation between the candidatetreatment protocols; and, wherein the first candidate treatment protocolhas a parameter value that is set to produce a stimulationcharacteristic that corresponds with a first characteristic ofendogenous electrical activity of a patient, and the second candidatetreatment protocol has a parameter value that is set to avoidstimulation that corresponds with the first characteristic of endogenouselectrical activity of the patient, and stimulating with only the firstprotocol is likely to have an unwanted side effect, and whereby thealternating decreases the likelihood of producing this side-effect. 2.The device of claim 1 wherein said alternation between candidatetreatment protocols comprises non-instantaneous roving between theparameter values of the protocols.
 3. The device of claim 1 wherein thethe first characteristic of endogenous electrical activity is sensed byat least one external sensor.
 4. The device of claim 1 wherein the firstsaid treatment protocol provides at least one stimulation signal toprovide stimulation to at least a first stimulation conduit and a secondtreatment protocol provides stimulation to at least a second stimulationconduit.
 5. The device of claim 1 wherein the disorder of the centralnervous system is epilepsy and said first candidate treatment protocolis configured for treating a particular type of symptom which is relatedto at least one of the type, location, spectral signature, size, andduration of epileptic activity.
 6. The device of claim 1, wherein thedisorder is a movement disorder and said first candidate treatmentprotocol is configured for treating a particular type of symptom whichis related to at least one of the type, location, size, and duration ofa movement disorder symptom.
 7. The device of claim 1, wherein thedisorder is disorder related to a least one of the following group ofbrain functions: learning, cognition, memory, sensing of pain, andattention of the patient.
 8. The device of claim 1 wherein saidside-effect is a decrement related to a least one of the following groupof brain functions: learning, cognition, memory, pain and attention ofthe patient.
 9. The device of claim 1, wherein said protocols are eachconfigured to stimulate with sinusoidal waveforms.
 10. The device ofclaim 1, wherein said at least one treatment parameter value produces astimulation signal having a dominant spectral profile betweenapproximately 0.5 Hz and 20 Hz.
 11. The device of claim 1, wherein thesecond candidate treatment protocol has a parameter value that causesstimulation to be halted for a selected duration.
 12. The device ofclaim 1 wherein at least one of the said candidate treatment protocolsis designed to deter a specific pattern of endogenous activity,associated with the disorder.
 13. The device of claim 1 wherein theendogenous electrical activity is related to at least one of: the brainand the heart.
 14. The device of claim 1, which additionally includes: asensor set including at least one sensor and a sensing subsystem forsensing data from the sensor to obtain sensed data, wherein the controlsubsystem is further configured for controlling the sensing subsystemand for providing processing of said sensed data in order to obtain atleast one sensed data result.
 15. The device of claim 14, wherein saidalternation occurs according to an algorithm so that the proportion oftime stimulating with each of the treatment protocols is related to theproportion of incidence of two or more symptoms, as calculated from theresults of processing of said sensed data.
 16. The device of claim 14,wherein the control subsystem is further configured for the adjustmentof one or more parameters of at least one candidate treatment protocolsaccording to the sensed data result.
 17. The device of claim 14, whereinthe parameter values of the first candidate treatment protocol is chosenas a value shown to produce a test score above a threshold criteria,said test score being computed using the results of processing of saidsensed data.
 18. A device of claim 17, wherein the test score is atremor score which is computed to indicate at least one of the count,duration, size, and type of a tremor.
 19. A device of claim 17, whereinthe test score is at least one seizure score which is computed toreflect at least one of the count, duration, size, and type of seizuresor seizure related activities.
 20. The device of claim 14, wherein thealternation between candidate treatment protocols occurs according to a‘rate of alternating’ parameter value that is modified according to thesensed data result, said value serving to adjust the rate ofalternation.
 21. The device of claim 14, wherein the adjustment of oneor more parameters is the adjustment of a delay parameter that sets thestimulation signal to be approximately out-of-phase with endogenousactivity and adds primarily constructively or destructively withendogenous activity.
 22. A device of claim 1 wherein each candidateprotocol is associated with a test score which is above at least aminimum score threshold, said test score being computed using at leastone of: sensed data which were processed and scored; imaging data whichwere processed and scored; and behavioral measures.
 23. The device ofclaim 1, wherein the alternating between candidate treatment protocolsoccurs according to a rate of alternating parameter that is selectedaccording to rates that produced test scores above a minimum scorethreshold, wherein different rates of alternating were assessed during acalibration session for the patient.
 24. The device of claim 1, whereinthe first candidate treatment protocols is selected to have a parametervalue that is within a specified range, said range being selected sothat the resulting stimulation signals produced by the treatmentprotocols matches spectral characteristics of selected types ofendogenous activity of the patient.
 25. A method for treating a disorderof the central nervous system comprising: implanting a conduit setcontaining at least one stimulation conduit including at least oneprobe; operating a stimulation subsystem to provide stimulation to theprobe according to one of at least two candidate treatment protocols,with each protocol having at least one treatment parameter value;operating a control subsystem to control the stimulation subsystem, saidcontrol subsystem operating under a treatment program designed foralternating to provide alternation between the candidate treatmentprotocols; and, wherein each candidate treatment protocol is directed toprimarily decrease a particular type of symptom related to the disorder,wherein the symptoms treated by each candidate protocol are differentsymptoms, wherein the first candidate treatment protocol has a parametervalue that is set to produce a stimulation characteristic thatcorresponds with a first characteristic of endogenous activity of apatient, and the second candidate treatment protocol has a parametervalue that is set to avoid corresponding with the first characteristicof endogenous activity of the patient, and stimulating with only thefirst protocol is likely to have an unwanted side effect, and wherebythe alternating decreases the likelihood of producing this side-effect.